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Green tea studies in the NaPDI repository

studyURL	id	naturalProduct.name	name	napdiIdentifier	overallSummary	pubmedId	embaseId	croIdentifier	croInformation	dateStart	dateEnd	internalComment	status	studySourceTypeId	studySourceType.id	studySourceType.name
http://repo.napdi.org/NPDI-kVw4tA	863	Green tea	When Green Becomes Mean: Green Tea Extract Reduces Ziprasidone's Effect and Causes Psychosis		Discussed a case report of a 23-year-old Asian man who had a potential drug-herb interaction between green tea and ziprasidone that led to psychotic symptoms.	31.995.673		N/A	N/A				published	4	4	Published Case Report
http://repo.napdi.org/NPDI-y64ahQ	864	Green tea	The effect of green tea on simvastatin tolerability		Discussed a 61-year-old man who had a potential herb-drug interaction between green tea and simvastatin that led to statin muscle intolerance.	18.711.168		N/A	N/A				published	4	4	Published Case Report
http://repo.napdi.org/NPDI-fvrNwA	865	Horny Goat Weed	Herba Epimedii and Increased Opioid Cravings While on Buprenorphine: A Case Report		Herba Epimedii, commonly known as yin yang huo, inyokaku, and horny goat weed, is a traditional Chinese herbal medicine utilized for treating osteoporosis and enhancing libido. Studies conducted in vitro have demonstrated that Herba Epimedii interacts with the enzyme cytochrome P450 3A4 (CYP3A4). This interaction poses a potential risk for drug-drug interactions, particularly with medications metabolized by CYP3A4, such as buprenorphine. This paper presents a case of a patient experiencing exacerbated opioid cravings following the initiation of Herba Epimedii. This is the first reported case supporting this interaction, emphasizing the necessity of screening for alternative medicines in patients undergoing medication-assisted treatments for opioid use disorder.	38.327.958		N/A	N/A				published	4	4	Published Case Report
http://repo.napdi.org/NPDI-7x0lVQ	746	Kratom	Fatal combination of mitragynine and quetiapine - a case report with discussion of a potential herb-drug interaction		A 27-year-old man with a past medical history significant for Asperger Syndrome, bipolar disorder, and substance abusewas found deceased inside his secured residence.	30.498.933		Did Not Include	University of North Dakota School of Medicine and Health Sciences, 1301 N. Columbia Rd (RoomW430), Grand Forks, ND 58203, USA				published	4	4	Published Case Report
http://repo.napdi.org/NPDI-WFgDZg	719	Ginger	Case Report: Fatigue and Bleeding in a Polymedicated Patient Using Several Herbal Supplementations		This was a case report of severe fatigue and bleeding in a 65-year-old man with ischemic heart disease who was wearing a stent and taking multiple medications for hypertension and diabetes. The use of a drug interaction and personalized prescription software (g-Nomic®) revealed potential interactions, involving acetylsalicylic acid and several non-pharmaceutical products including ginger, blueberry extracts, pineapple juice, docosahexaenoic acid and liquorice.	34.408.471		Did Not Include	Bahía de Cádiz-La Janda Health District, Mobile Emergency Unit of the Andalusian Health Care, Service of Cádiz, Cádiz, Spain				published	4	4	Published Case Report
http://repo.napdi.org/NPDI-WFgDZg	719	Ginger	Case Report: Fatigue and Bleeding in a Polymedicated Patient Using Several Herbal Supplementations		This was a case report of severe fatigue and bleeding in a 65-year-old man with ischemic heart disease who was wearing a stent and taking multiple medications for hypertension and diabetes. The use of a drug interaction and personalized prescription software (g-Nomic®) revealed potential interactions, involving acetylsalicylic acid and several non-pharmaceutical products including ginger, blueberry extracts, pineapple juice, docosahexaenoic acid and liquorice.	34.408.471		Did Not Include	Bahía de Cádiz-La Janda Health District, Mobile Emergency Unit of the Andalusian Health Care, Service of Cádiz, Cádiz, Spain				published	4	4	Published Case Report
http://repo.napdi.org/NPDI-azPVSg	860	Barbary matrimony-vine	Flecainide toxicity associated with the use of goji berries: a case report: warfarin		Background: Goji berries (GB), usually marketed as a 'superfruit', are a widely used herbal supplement. As with other herbal remedies, the use of GB might be associated with herb-drug interactions, increasing plasma levels of other drugs and causing adverse events. Here, we present the case of a patient that developed flecainide toxicity secondary to an herb-drug interaction, associated with the use of GB to prevent COVID-19. Case summary: A 75-year-old female presented to the emergency department with fainting. She was taking flecainide for the treatment of atrial extrasystoles diagnosed 2 years previously, and she was using a tea of GB for the prevention of COVID-19. The admission electrocardiogram showed a wide complex polymorphic tachycardia that was considered and treated as flecainide toxicity. The patient had a favourable evolution and was discharged 48 h after admission. Discussion: Flecainide toxicity is uncommon and needs timely recognition and treatment; it is usually secondary to overdose and renal or hepatic failure. In our case, toxicity was associated with GB use, probably by inhibition of CYP2D6 which is the main enzyme associated with the metabolism of flecainide. Clinicians need to be aware of the possible interactions between herbal remedies (in this case used for the prevention of COVID-19) and cardiovascular drugs that are used to treat chronic cardiovascular diseases.	34.084.998		N/A	N/A				published	4	4	Published Case Report
http://repo.napdi.org/NPDI-veOxuw	861	Barbary matrimony-vine	Flecainide toxicity associated with the use of goji berries: a case report: flecainide		Background: Goji berries (GB), usually marketed as a 'superfruit', are a widely used herbal supplement. As with other herbal remedies, the use of GB might be associated with herb-drug interactions, increasing plasma levels of other drugs and causing adverse events. Here, we present the case of a patient that developed flecainide toxicity secondary to an herb-drug interaction, associated with the use of GB to prevent COVID-19. Case summary: A 75-year-old female presented to the emergency department with fainting. She was taking flecainide for the treatment of atrial extrasystoles diagnosed 2 years previously, and she was using a tea of GB for the prevention of COVID-19. The admission electrocardiogram showed a wide complex polymorphic tachycardia that was considered and treated as flecainide toxicity. The patient had a favourable evolution and was discharged 48 h after admission. Discussion: Flecainide toxicity is uncommon and needs timely recognition and treatment; it is usually secondary to overdose and renal or hepatic failure. In our case, toxicity was associated with GB use, probably by inhibition of CYP2D6 which is the main enzyme associated with the metabolism of flecainide. Clinicians need to be aware of the possible interactions between herbal remedies (in this case used for the prevention of COVID-19) and cardiovascular drugs that are used to treat chronic cardiovascular diseases.	34.084.998		N/A	N/A				published	4	4	Published Case Report
http://repo.napdi.org/NPDI-ZfxNfg	106	Goldenseal	Vectorial transport of the plant alkaloid berberine by double-transfected cells expressing the human organic cation transporter 1 (OCT1, SLC22A1) and the efflux pump MDR1 P-glycoprotein (ABCB1)	PMID: 18157518	An important function of hepatocytes is the biliary elimination of endogenous and xenobiotic small molecules, many of which are organic cations. To study this vectorial transport of organic cations, we constructed a double-transfected Madin-Darby canine kidney strain II (MDCKII) cell line permanently expressing the human organic cation transporter 1 (OCT1, SLC22A1) in the basolateral membrane and MDR1 P-glycoprotein (MDR1 P-gp, ABCB1), an adenosine triphosphate (ATP)-dependent efflux pump for organic cations, in the apical membrane. Additionally, MDCKII single transfectants stably expressing OCT1, MDR1 P-gp, or human organic cation transporter 2 (OCT2, SLC22A2) were generated. Antisera directed against OCT1 or OCT2 specifically detected OCT1 in the basolateral membrane of human hepatocytes, OCT2 in tubular epithelial cells of human kidney, and the respective recombinant transporter in the basolateral membrane of MDCKII transfectants. We identified the lipophilic organic cation berberine, a fluorescent plant alkaloid exhibiting a broad range of biological activities, as substrate of OCT1 and OCT2 with Michaelis-Menten constants of 14.8 μM and 4.4 μM, respectively. Berberine also inhibited the uptake of the prototypic cations tetraethylammo- nium and 1-methyl-4-phenylpyridinium by MDCK-OCT1 and MDCK-OCT2 transfectants. When transfected cells were grown polarized on permeable filter supports, berberine was transferred from the basolateral to the apical compartments many times faster by MDCK-OCT1/MDR1 P-gp double transfectants than by MDCK-OCT1 or MDCK-MDR1 P-gp single transfectants. The specific MDR1 P-gp inhibitor, zosuquidar trihydrochloride (LY335979), strongly inhibited berberine efflux into the apical compartment. The MDCK- OCT1/MDR1 P-gp double transfectants may be useful to identify additional cationic substrates and inhibitors of OCT1 and MDR1 P-gp, including drug candidates.	18.157.518		German Cancer Research Center	Division of Tumor Biochemistry				published	1	1	Published report
http://repo.napdi.org/NPDI-CWch6w	802	Licorice	Chemical basis of pregnane X receptor activators in the herbal supplement Gancao (licorice)		Gancao, also known as licorice, has numerous beneficial pharmacological effects. Data regarding herb-drug interactions via hPXR and CYP3A4 with licorice is limited. Gancao extract seemed to activate hPXR, but has a weak effect on CYP3A4 in vivo. CYP3A4 and hPXR effects of bioactive components, glycyrrhizin and glycyrrhetinic acid, were also studied. Glycyrrhizin results showed no activation of hPXR in vivo or in vitro. Glycyrrhetinic acid showed no activation of hPXR in vitro, but it activated hPXR and induced CYP3A4 in vivo. Glabridin, another chemical compound found in licorice, showed mild PXR activation and moderate upregulation of CYP3A4.			U Pitt, WSU-1	Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh; Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University				published	1	1	Published report
http://repo.napdi.org/NPDI-m8Wl_w	807	Horny Goat Weed	Horny goat weed aerial parts extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-horny-goat-weed-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-sv6smA	151	Goldenseal	Goldenseal Metabolomics		LC-MS metablomics and composite score analysis [1,2] was used to compare the chemical composition of 35 commercial H. canadensis samples. A single sample (dried Hydrastis canadensis room material, arbitrarily identified as GS-16) was chosen for use in pharmacology studies based on its similarity to authentic reference standards and to other commercially used goldenseal supplements. 1. Joshua J. Kellogg, Olav M. Kvalheim, Nadja B. Cech, Composite score analysis for unsupervised comparison and network visualization of metabolomics data,Analytica Chimica Acta, Volume 1095, 2020, Pages 38-47, ISSN 0003-2670, https://doi.org/10.1016/j.aca.2019.10.029. 2. Wallace ED, Oberlies NH, Cech NB, Kellogg JJ. Detection of adulteration in Hydrastis canadensis (goldenseal) dietary supplements via untargeted mass spectrometry-based metabolomics. Food Chem Toxicol. 2018;120:439-447. doi:10.1016/j.fct.2018.07.033.			UNCG	University of North Carolina - Greensboro				published	2	2	Manuscript prepared or submitted for peer-reviewed publication
http://repo.napdi.org/NPDI-cM9pfg	119	Cannabis	The effects of cannabinoids on P-glycoprotein transport and expression in multidrug resistant cells.	PMID: 16458258	Cannabis is the most widely used illicit drug in the world. Cannabinoids are used therapeutically by some patients as they have analgesic, anti-emetic and appetite stimulant properties which palliate adverse symptoms. Use of these agents in an oncology setting raises the question of whether they act to modulate the effectiveness of concurrently administered anti-cancer drugs. The transporter, P-glycoprotein (P-gp) confers multiple drug resistance (MDR) by effluxing a diverse array of anti-cancer agents. This study was undertaken to examine the effect of cannabinoids on P-gp. Unlike the known P-gp inhibitor, PSC833, short 1h exposure to three plant-derived cannabinoids, cannabinol (CBN), cannabidiol (CBD) and Delta(9)-tetrahydrocannabinol (THC) and the synthetic cannabinoid receptor agonist, WIN55, 212-2 (WIN) did not inhibit the efflux of the P-gp substrate Rhodamine 123 (Rh123) in either a drug-selected human T lymphoblastoid leukaemia cell line (CEM/VLB(100)) or in a mouse fibroblast MDR1 transfected cell line (77.1). However, in CEM/VLB(100) cells, prolonged 72 h exposure to the cannabinoids, THC and CBD, decreased P-gp expression to a similar extent as the flavonoid, curcumin (turmeric). This correlated with an increase in intracellular accumulation of Rh123 and enhanced sensitivity of the cells to the cytotoxic actions of the P-gp substrate, vinblastine. Taken together, these results provide preliminary evidence that cannabinoids do not exacerbate P-gp mediated MDR. Further, plant-derived cannabinoids are moderately effective in reversing MDR in CEM/VLB(100) cells by decreasing P-gp expression.	16.458.258		Department of Pharmacology	The University of Sydney				published	1	1	Published report
http://repo.napdi.org/NPDI-vhBMSw	101	Cannabis	Involvement of UDP-Glucuronosyltransferases UGT1A9 and UGT2B7 in Ethanol Glucuronidation, and Interactions with Common Drugs of Abuse	PMID: 23230132	Ethyl glucuronide (EtG) determination is increasingly used in clinical and forensic toxicology to document ethanol consumption. The enzymes involved in EtG production, as well as potential interactions with common drugs of abuse, have not been extensively studied. Activities of human liver (HLM), kidney (HKM), and intestinal (HIM) microsomes, as well as of 12 major human recombinant UDP-glucuronosyltransferases (UGTs), toward ethanol (50 and 500 mM) were evaluated in vitro using liquid chromatography-tandem mass spectrometry. Enzyme kinetic parameters were determined for pooled microsomes and recombinant UGTs with significant activity. Individual contributions of UGTs were estimated using the relative activity factor approach, proposed for scaling activities obtained with cDNA-expressed enzymes to HLM. Interaction of morphine, codeine, lorazepam, oxazepam, nicotine, cotinine, cannabinol, and cannabidiol (5, 10, 15 mg/l) with ethanol (1.15, 4.6, 11.5 g/l; i.e., 25, 100, 250 mM) glucuronidation was assessed using pooled HLM. Ethanol glucuronidation intrinsic clearance (Cl(int)) was 4 and 12.7 times higher for HLM than for HKM and HIM, respectively. All recombinant UGTs, except UGT1A1, 1A6, and 1A10, produced EtG in detectable amounts. UGT1A9 and 2B7 were the most active enzymes, each accounting for 17 and 33% of HLM Cl(int), respectively. Only cannabinol and cannabidiol significantly affected ethanol glucuronidation. Cannabinol increased ethanol glucuronidation in a concentration-dependent manner, whereas cannabidiol significantly inhibited EtG formation in a noncompetitive manner (IC(50) = 1.17 mg/l; inhibition constant (K(i)) = 3.1 mg/l). UGT1A9 and 2B7 are the main enzymes involved in ethanol glucuronidation. In addition, our results suggest that cannabinol and cannabidiol could significantly alter ethanol glucuronidation.	23.230.132		EA4483	Université Lille-Nord de France				published	1	1	Published report
http://repo.napdi.org/NPDI-1wiJBw	137	Cannabis	Cannabidiol changes P-gp and BCRP expression in trophoblast cell lines.		Objectives.Marijuana is the most commonly used illicit drug during pregnancy. Due to high lipophilicity, cannabinoids can easily penetrate physiological barriers like the human placenta and jeopardize the developing fetus.We evaluated the impact of cannabidiol (CBD), a major non-psychoactive cannabinoid, on P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) expression, and P-gp function in a placental model, BeWo and Jar choriocarcinoma cell lines (using P-gp induced MCF7 cells (MCF7/P-gp) for comparison). Study design. Following the establishment of the basal expression of these transporters in the membrane fraction of all three cell lines, P-gp and BCRP protein and mRNA levels were determined following chronic (24–72 h) exposure to CBD, by Western Blot and qPCR. CBD impact on P-gp efflux function was examined by uptake of specific P-gp fluorescent substrates (calcein-AM, DiOC2(3) and rhodamine123( rh123)). Cyclosporine A (CsA) served as a positive control. Results. Chronic exposure to CBD resulted in significant changes in the protein and mRNA levels of both transporters. While P-gp was down-regulated, BCRP levels were up-regulated in the choriocarcinoma cell lines. CBD had a remarkably different influence on P-gp and BCRP expression in MCF7/P-gp cells, demonstrating that these are cell type specific effects. P-gp dependent efflux (of calcein, DiOC2(3) and rh123) was inhibited upon short-termexposure to CBD. Conclusions. Our study shows that CBD might alter P-gp and BCRP expression in the human placenta, and inhibit P-gp efflux function.We conclude that marijuana use during pregnancy may reduce placental protective functions and change its morphological and physiological characteristics.	24.058.883		Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev , Israel	Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev , Israel			A published report from the literature. Data entered by CB and review by RB.	published	1	1	Published report
http://repo.napdi.org/NPDI-oEAKVw	168		Inhibition of CYP enzymes by licochalcone a		The potential of licorice dietary supplements to interact with drug metabolism was evaluated by testing extracts of three botanically identified licorice species (Glycyrrhiza glabra L., Glycyrrhiza uralensis Fish. ex DC. and Glycyrrhiza inflata Batalin) and 14 isolated licorice compounds for inhibition of 9 cytochrome P450 enzymes using a UHPLC-MS/MS cocktail assay. G. glabra showed moderate inhibitory effects against CYP2B6, CYP2C8, CYP2C9, and CYP2C19, and weak inhibition against CYP3A4 (testosterone). In contrast, G. uralensis strongly inhibited CYP2B6 and moderately inhibited CYP2C8, CYP2C9 and CYP2C19, and G. inflata strongly inhibited CYP2C enzymes and moderately inhibited CYP1A2, CYP2B6, CYP2D6, and CYP3A4 (midazolam). The licorice compounds isoliquiritigenin, licoricidin, licochalcone A, 18β-glycyrrhetinic acid, and glycycoumarin inhibited one or more members of the CYP2C family of enzymes. Glycycoumarin and licochalcone A inhibited CYP1A2, but only glycycoumarin inhibited CYP2B6. Isoliquiritigenin, glabridin and licoricidin competitively inhibited CYP3A4, while licochalcone A (specific to G. inflata roots) was a mechanism-based inhibitor. The three licorice species commonly used in botanical dietary supplements have varying potential for drug-botanical interactions as inhibitors of cytochrome P450 isoforms. Each species of licorice displays a unique profile of constituents with potential for drug interactions.	28.774.812		UIC	UIC	22/03/2017 12:00 AM	30/07/2017 12:00 AM		published	1	1	Published report
http://repo.napdi.org/NPDI-rREhEQ	93	Goldenseal	Tetrandrine Potentiates the Hypoglycemic Efficacy of Berberine by Inhibiting P-Glycoprotein Function	PMID: 23924821	This study was designed to improve the absorption and hypoglycemic efficacy of berberine (BBR), which is a substrate of P-glycoprotein (P-gp), by combination with a P-gp inhibitor tetrandrine (Tet). Flow cytometry and LC-MS/MS were used to determine the cellular efflux or retention of chemicals. Pharmacokinetic study was performed in ICR mice following oral administration of the study compounds. The hypoglycemic efficacies of the compounds were evaluated in diabetic KK-Ay mice. In the in vitro experiments, Tet significantly inhibited the efflux and increased the uptake of P-gp substrates rhodamine-123 as well as BBR in MCF7/DOX cells and Caco-2 intestinal cells. Meanwhile, Tet greatly reduced the expression of P-gp in Caco-2 cells. The inhibition of BBR efflux by Tet was translated into improved pharmacokinetics in vivo. When co-administered, Tet dose-dependently increased the average maximum concentration (Cmax) and area under concentration–time curve (AUC0–24) of BBR in mice. Tet itself had no impact on glucose metabolism. However, it greatly potentiated the hypoglycemic efficacy of BBR in diabetic KK-Ay mice. In addition, we found that Tet had moderate inhibitory effect on the catalytic activity of CYP3A4, which played a role in the bio-transformation of BBR, and this may also take part in the improvement of the pharmacokinetics of BBR. In summary, combination with P-gp inhibitors such as Tet can improve the pharmacokinetics and hypoglycemic efficacy of BBR greatly; this implicates a feasible strategy for exploring the therapeutic effects of BBR and other pharmaceuticals which are substrates of P-gp.	23.924.821		Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College	Department of Pharmacology				published	1	1	Published report
http://repo.napdi.org/NPDI-e2Zw7w	825	Ashwaganda	Ashwagandha root extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-ashwagandha-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-yA7l_g	805	Beet root	Beet root leaf extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-AHR-beet-root-1	Natural Center for Natural Products Research			PXR fold activation results not available	published	1	1	Published report
http://repo.napdi.org/NPDI-KpNlwA	815	Maca	Maca root extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-AHR-maca-1	Natural Center for Natural Products Research			PXR fold activation results not available	published	1	1	Published report
http://repo.napdi.org/NPDI-utgZiA	11	Green tea	Plasma pharmacokinetics of catechin metabolite 4'-O-Me-EGC in healthy humans	PMID:21212969	BACKGROUND: Tea is an infusion of the leaves of the Camellia sinensis plant and is the most widely consumed beverage in the world after water. Green tea contains significant amounts of polyphenol catechins and represents a promising dietary component to maintain health and well-being. Epidemiological studies indicate that polyphenol intake may have potential health benefits, such as, reducing the incidence of coronary heart disease, diabetes and cancer. While bioavailability of green tea bioactives is fairly well understood, some gaps still remain to be filled, especially the identification and quantification of conjugated metabolites in plasma, such as, sulphated, glucuronidated or methylated compounds. AIM OF THE STUDY: In the present study, we aimed to quantify the appearance of green tea catechins in plasma with particular emphasis on their methylated forms. RESULTS: After feeding 400 mL of green tea, 1.25% infusion to 9 healthy subjects, we found significant amounts of EC, EGC and EGCg in plasma as expected. EGC was the most bioavailable catechin, and its methylated form (4'-O-Me-EGC) was also present in quantifiable amounts. Its kinetics followed that of its parent compound. However, the relative amount of the methylated form of EGC was lower than that of the parent compound, an important aspect which, in the literature, has been controversial so far. The quantitative results presented in our study were confirmed by co-chromatography and accurate mass analysis of the respective standards. We show that the relative abundance of 4'-O-Me-EGC is ~40% compared to the parent EGC. CONCLUSION: 4'-O-Me-EGC is an important metabolite derived from catechin metabolism. Its presence in significant amounts should not be overlooked when assessing human bioavailability of green tea.	21.212.969		Nestle	Nestle Research Center, Nestec Ltd.			This is a study reported in the literature. The data was entered by JS and reviewed by JY.	published	1	1	Published report
http://repo.napdi.org/NPDI-SiYA_A	131	Cannabis	Drug Approval Package: Epidiolex (Cannabidiol)	FDA: 210365 Orig 1	U.S. Food and Drug Administration https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210365Orig1s000TOC.cfm			GW Research Ltd.	GW Research Ltd.				published	1	1	Published report
http://repo.napdi.org/NPDI-uLn5Ig	812	Barley grass	Barley grass seed extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-AHR-barley-grass-1	Natural Center for Natural Products Research			PXR fold activation results not available	published	1	1	Published report
http://repo.napdi.org/NPDI-xYeUJQ	66	Cannabis	Influence of cannabidiol on secobarbital effects and plasma kinetics	PMID: 791563	To investigate the possible metabolic interaction between cannabidiol (CBD) and secobarbital, 6 male volunteers received 150 mg/70 kg sodium secobarbital orally immediately after smoking a marihuana cigarette prepared to deliver 0, 150, or 500 µg/kg CBD. The study was performed in a double-blind manner with each of the three treatments being assigned to every subject. Clinical effects and plasma secobarbital concentrations were recorded at periodic intervals. CBD did not alter the summary parameters which describe the secobarbital plasma concentration time curve. Secobarbital half-life, peak concentration, time of peak concentration, and area under the curve were unchanged by the coadministration of CBD. Clinical effects of secobarbital were also unaltered by CBD pretreatment. Thus at the doses administered, CBD does not appear to inhibit secobarbital metabolism in man.	791.563		Indiana University School of Medicine	Indiana University School of Medicine				published	1	1	Published report
http://repo.napdi.org/NPDI-uPn_2w	142	Cannabis	Enhanced biotransformation of theophylline in marihuana and tobacco smokers.		Single oral doses of theophylline were administered to 7 chronic marihuana smokers, to 7 chronic users of both marihuana and tobacco, and to 43 appropriate control subjects. Theophylline was cleared from the blood more rapidly in both marihuana and tobacco smokers with a mean increase in total clearance from 52 ml/kg/hr in nonsmokers to 74 ml/kg/hr in subjects who smoked either material alone. There was an additive increase in clearance to 93 ml/kg/hr in those who smoked both substances. Concern over enhanced metabolism of other drugs is probably warranted in tobacco and cannabis smokers.	688.731		Clinical Pharmacokinetics Laboratory, Departments of Pharmaceutics and Medicine, Millard Fillmore Hospital and State University of New York at Buffalo	Clinical Pharmacokinetics Laboratory, Departments of Pharmaceutics and Medicine, Millard Fillmore Hospital and State University of New York at Buffalo			A published report from the literature. Data entered by CB and review by RB.	published	1	1	Published report
http://repo.napdi.org/NPDI--UmauA	827	Cat's-claw	Identification of PXR activators from Uncaria tomentosa (Cat’s Claw)		Cat's Claw extracts were found to dose-dependently activate PXR and induce CYP3A4 expression. New activators from Cat's Claw were also discovered and demonstrated the half maximal effective concentration < 10 µM for PXR activation. Isocorynoxeine, rhynchophylline, isorhynchophylline, corynoxeine, isopteropodine, pteropodine, and mitraphylline were identified as PXR activators from Cat’s Claw extracts.	36.797.057		U Pitt, Duquesne-1	Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh; Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University				published	1	1	Published report
http://repo.napdi.org/NPDI-JI5m9A	816	Horehound	Horehound leaf extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-horehound-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-iHWMgQ	109	Cannabis	Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety.	PMID: 21356216	AIMS: In this study, we examined the inhibitory effects of Δ(9)-tetrahydrocannabinol (Δ(9)-THC), cannabidiol (CBD), and cannabinol (CBN), the three major cannabinoids, on the activity of human cytochrome P450 (CYP) 3A enzymes. Furthermore, we investigated the kinetics and structural requirement for the inhibitory effect of CBD on the CYP3A activity. MAIN METHODS: Diltiazem N-demethylase activity of recombinant CYP3A4, CYP3A5, CYP3A7, and human liver microsomes (HLMs) in the presence of cannabinoids was determined. KEY FINDINGS: Among the three major cannabinoids, CBD most potently inhibited CYP3A4 and CYP3A5 (IC(50)=11.7 and 1.65 μM, respectively). The IC(50) values of Δ(9)-THC and CBN for CYP3A4 and CYP3A5 were higher than 35 μM. For CYP3A7, Δ(9)-THC, CBD, and CBN inhibited the activity to a similar extent (IC(50)=23-31 μM). CBD competitively inhibited the activity of CYP3A4, CYP3A5, and HLMs (K(i)=1.00, 0.195, and 6.14 μM, respectively). On the other hand, CBD inhibited the CYP3A7 activity in a mixed manner (K(i)=12.3 μM). Olivetol partially inhibited all the CYP3A isoforms tested, whereas d-limonene showed lack of inhibition. The lesser inhibitory effects of monomethyl and dimethyl ethers of CBD indicated that the ability of CYP3A inhibition by the cannabinoid attenuated with the number of methylation on the phenolic hydroxyl groups in the resorcinol moiety. SIGNIFICANCE: This study indicated that CBD most potently inhibited catalytic activity of human CYP3A enzymes, especially CYP3A4 and CYP3A5. These results suggest that two phenolic hydroxyl groups in the resorcinol moiety of CBD may play an important role in the CYP3A inhibition.	21.356.216		Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences,	Hokuriku University				published	1	1	Published report
http://repo.napdi.org/NPDI-3p6SkQ	817	Moringa	Moringa leaf extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-moringa-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-zg6Npw	12	Green tea	Inhibitory effects of commonly used herbal extracts on UDP-glucuronosyltransferase 1A4, 1A6, and 1A9 enzyme activities	PMID:21632963	The aim of this study was to investigate the effect of commonly used botanicals on UDP-glucuronosyltransferase (UGT) 1A4, UGT1A6, and UGT1A9 activities in human liver microsomes. The extracts screened were black cohosh, cranberry, echinacea, garlic, ginkgo, ginseng, milk thistle, saw palmetto, and valerian in addition to the green tea catechin epigallocatechin gallate (EGCG). Formation of trifluoperazine glucuronide, serotonin glucuronide, and mycophenolic acid phenolic glucuronide was used as an index reaction for UGT1A4, UGT1A6, and UGT1A9 activities, respectively, in human liver microsomes. Inhibition potency was expressed as the concentration of the inhibitor at 50% activity (IC(50)) and the volume in which the dose could be diluted to generate an IC(50)-equivalent concentration [volume/dose index (VDI)]. Potential inhibitors were EGCG for UGT1A4, milk thistle for both UGT1A6 and UGT1A9, saw palmetto for UGT1A6, and cranberry for UGT1A9. EGCG inhibited UGT1A4 with an IC(50) value of (mean ± S.E.) 33.8 ± 3.1 μg/ml. Milk thistle inhibited both UGT1A6 and UGT1A9 with IC(50) values of 59.5 ± 3.6 and 33.6 ± 3.1 μg/ml, respectively. Saw palmetto and cranberry weakly inhibited UGT1A6 and UGT1A9, respectively, with IC(50) values >100 μg/ml. For each inhibition, VDI was calculated to determine the potential of achieving IC(50)-equivalent concentrations in vivo. VDI values for inhibitors indicate a potential for inhibition of first-pass glucuronidation of UGT1A4, UGT1A6, and UGT1A9 substrates. These results highlight the possibility of herb-drug interactions through modulation of UGT enzyme activities. Further clinical studies are warranted to investigate the in vivo extent of the observed interactions.	21.632.963		UF	University of Flordia			This is a study reported in the literature. The data was entered by JS and reviewed by JY.	published	1	1	Published report
http://repo.napdi.org/NPDI-7LwuzA	10	Green tea	Inhibitory Effects of Green Tea and (-)-Epigallocatechin Gallate on Transport by OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K and P-Glycoprotein	PMID:26426900	Green tea catechins inhibit the function of organic anion transporting polypeptides (OATPs) that mediate the uptake of a diverse group of drugs and endogenous compounds into cells. The present study was aimed at investigating the effect of green tea and its most abundant catechin epigallocatechin gallate (EGCG) on the transport activity of several drug transporters expressed in enterocytes, hepatocytes and renal proximal tubular cells such as OATPs, organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), and P-glycoprotein (P-gp). Uptake of the typical substrates metformin for OCTs and MATEs and bromosulphophthalein (BSP) and atorvastatin for OATPs was measured in the absence and presence of a commercially available green tea and EGCG. Transcellular transport of digoxin, a typical substrate of P-gp, was measured over 4 hours in the absence and presence of green tea or EGCG in Caco-2 cell monolayers. OCT1-, OCT2-, MATE1- and MATE2-K-mediated metformin uptake was significantly reduced in the presence of green tea and EGCG (P < 0.05). BSP net uptake by OATP1B1 and OATP1B3 was inhibited by green tea [IC50 2.6% (v/v) and 0.39% (v/v), respectively]. Green tea also inhibited OATP1B1- and OATP1B3-mediated atorvastatin net uptake with IC50 values of 1.9% (v/v) and 1.0% (v/v), respectively. Basolateral to apical transport of digoxin was significantly decreased in the presence of green tea and EGCG. These findings indicate that green tea and EGCG inhibit multiple drug transporters in vitro. Further studies are necessary to investigate the effects of green tea on prototoypical substrates of these transporters in humans, in particular on substrates of hepatic uptake transporters (e.g. statins) as well as on P-glycoprotein substrates.	26.426.900		na	University of Erlangen Nuremberg			This is a study reported in the literature. The data was entered by JS and reviewed by JY.	published	1	1	Published report
http://repo.napdi.org/NPDI-2P3dUg	146	Cannabis	Cannabis extract (THC) Characterization of Material		Certificate of Analysis from RTI Log number 13946-0715-8 on June 2016			WSU	WSU				published	3	3	Unpublished data submitted through a NaPDI form
http://repo.napdi.org/NPDI-ahQtSQ	139	Cannabis	Interaction of plant cannabinoids with the multidrug transporter ABCC1 (MRP1)		The ATP-binding cassette (ABC) transporter ABCC1, or multidrug resistance-related protein 1 (MRP1) is implicated in Phase II metabolism and multidrug resistance as it effluxes substrate anticancer drugs. As cannabinoids inhibit two related ABC transporters, P-glycoprotein and ABCG2, here we examined whether they also inhibit ABCC1. Indeed, the cannabinoids enhanced the intracellular accumulation of two ABCC1 substrates, Fluo3 and vincristine, in ovarian carcinoma cells over-expressing ABCC1 (2008/MRP1) with a rank order of potency: cannabidiol>cannabinol>Delta(9)-tetrahydrocannabinol. Cannabinoid inhibition of ABCC1 was confirmed using insect cell membrane MRP1 ATPase assays. These results demonstrate that cannabinoids inhibit ABCC1.	18.619.955		School of Medical Sciences (Pharmacology) and Bosch Institute, The University of Sydney, New South Wales, Australia	School of Medical Sciences (Pharmacology) and Bosch Institute, The University of Sydney, New South Wales, Australia			A published report from the literature. Data entered by CB and review by RB.	published	1	1	Published report
http://repo.napdi.org/NPDI-d8OUzg	143	Kratom	Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations		All kratom extracts inhibited CYP2C9, CYP2D6 and CYP3A (hepatic and intestinal) activities by similar extents, indicating minimal product to product variability with respect to CYP inhibition. Mitragynine inhibited CYP2C9, CYP2D6, and CYP3A activity by greater than 50%, warranting further investigation as a reversible or a time dependent inhibitor of the CYP activities. The 7-fold shift observed with mitragynine against intestinal and hepatic CYP3A activity suggests mitragynine is a time dependent inhibitor. IC₅₀values were within the concentration range reported in post-mortem human plasma and tissues. Although no leftward shift was observed for CYP2D6, the IC₅₀was also within the concentration range reported in post-mortem human plasma and tissues. Mitragynine was shown to be a strong competitive inhibitor of CYP2D6 activity. The robust K_i(~1 µM) will be applied to mechanistic and PBPK models to predict drug interaction potential. Mitragynine is a time dependent inhibitor of both intestinal and hepatic CYP3A activity. The efficiency of inactivation (k_inact/K_I) was similar to that of the clinically relevant time dependent inhibitor verapamil. The kinetic parameters, K_Iand k_inactwill be applied to mechanistic and PBPK models to predict drug interaction potential.	33.093.187		Washington State University	Washington State University			Data entered by CB and review by RB.	published	1	1	Published report
http://repo.napdi.org/NPDI-O4gNrA	193	Goldenseal	A clinical study of transporter-mediated goldenseal drug interactions		Effects of the goldenseal product on the efflux transporter breast cancer resistance protein (BCRP) and uptake transporters organic anion transporting polypeptide (OATP) 1B1/3, as well as organic anion transporters (OATs), organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), and CYP3A, were next evaluated in 16 healthy volunteers using a cocktail approach.	33.174.626		DPS-WSU-004	WSU	01/03/2018 12:00 AM	28/08/2020 12:00 AM	Dates of the study are approximate	published	1	1	Published report
http://repo.napdi.org/NPDI-bQlJCA	167		Inhibition of CYP enzymes by isoliquiritigenin		The potential of licorice dietary supplements to interact with drug metabolism was evaluated by testing extracts of three botanically identified licorice species (Glycyrrhiza glabra L., Glycyrrhiza uralensis Fish. ex DC. and Glycyrrhiza inflata Batalin) and 14 isolated licorice compounds for inhibition of 9 cytochrome P450 enzymes using a UHPLC-MS/MS cocktail assay. G. glabra showed moderate inhibitory effects against CYP2B6, CYP2C8, CYP2C9, and CYP2C19, and weak inhibition against CYP3A4 (testosterone). In contrast, G. uralensis strongly inhibited CYP2B6 and moderately inhibited CYP2C8, CYP2C9 and CYP2C19, and G. inflata strongly inhibited CYP2C enzymes and moderately inhibited CYP1A2, CYP2B6, CYP2D6, and CYP3A4 (midazolam). The licorice compounds isoliquiritigenin, licoricidin, licochalcone A, 18β-glycyrrhetinic acid, and glycycoumarin inhibited one or more members of the CYP2C family of enzymes. Glycycoumarin and licochalcone A inhibited CYP1A2, but only glycycoumarin inhibited CYP2B6. Isoliquiritigenin, glabridin and licoricidin competitively inhibited CYP3A4, while licochalcone A (specific to G. inflata roots) was a mechanism-based inhibitor. The three licorice species commonly used in botanical dietary supplements have varying potential for drug-botanical interactions as inhibitors of cytochrome P450 isoforms. Each species of licorice displays a unique profile of constituents with potential for drug interactions.	28.774.812		UIC	UIC	22/03/2017 12:00 AM	30/07/2017 12:00 AM		published	1	1	Published report
http://repo.napdi.org/NPDI-ZqVOgw	64	Cannabis	Interaction between naltrexone and oral THC in heavy marijuana smokers	PMID: 12491025	Rationale: Studies in non-human animals sug- gest that opioid antagonists block the reinforcing effects of cannabinoids. Objective: The present studies in humans investigated how naltrexone modulates (1) the subjective and physiological effects of oral THC in comparison to methadone, (2) the reinforcing effects of oral THC, and (3) plasma levels of oral THC. Methods: In study 1, marijuana smokers (n=9) received naltrexone (0, 50 mg) followed 30 min later by THC (0, 15, 30 mg) or methadone (5, 10 mg). Subjective effects, task perfor- mance, pupillary diameter, and cardiovascular parameters were measured repeatedly. In study 2a, marijuana smok- ers (n=23) were randomly assigned to one THC dose condition (0, 15 or 30 mg). One set of color-coded capsules containing THC and active naltrexone (50 mg) was given in one session, while another set of color-coded capsules containing THC and placebo naltrexone was given in another session. In the final three sessions, participants chose which color capsules they would receive. In study 2b, a subset of participants from study 2a (n=7) received naltrexone (0, 50 mg) 30 min prior to oral THC (30 mg) administration, and blood was drawn repeatedly. Results: Pretreatment with naltrexone signif- icantly increased many of the “positive” subjective effects of oral THC (30 mg) e.g. ratings of Good Drug Effect and Capsule Liking. Naltrexone tended to increase the reinforcing effects of oral THC (30 mg), as indicated by performance in a drug choice test. Naltrexone did not alter plasma THC levels. Conclusions: These studies demon- strate that naltrexone increases the subjective effects of oral THC. Thus, oral THC’s effects are enhanced rather than antagonized by opioid receptor blockade in heavy marijuana smokers.	12.491.025		New York State Psychiatric Institute	New York State Psychiatric Institute				published	1	1	Published report
http://repo.napdi.org/NPDI-i4m0FA	145	Cannabis	Cannabis Characterization of Bulk Plant Material					WSU	WSU	01/07/0201 12:00 AM	01/07/2018 12:00 AM	Data entered by CB with a COA provided by WSU.	published	3	3	Unpublished data submitted through a NaPDI form
http://repo.napdi.org/NPDI-vniY7Q	104	Cannabis	Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity.	PMID: 22166891	Inhibitory effects of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), cannabidiol (CBD), and cannabinol (CBN), the three major constituents in marijuana, and polycyclic aromatic hydrocarbons (PAHs) contained in marijuana smoke on catalytic activity of human cytochrome P450 (CYP) 2C9 were investigated. These phytocannabinoids concentration-dependently inhibited S-warfarin 7-hydroxylase and diclofenac 4'-hydroxylase activities of human liver microsomes (HLMs) and recombinant CYP2C9 (rCYP2C9). In contrast, none of the twelve PAHs including benz[a]anthracene and benzo[a]pyrene exerted substantial inhibition (IC₅₀ > 10 µM). The inhibitory potentials of Δ⁹-THC (Ki = 0.937-1.50 µM) and CBN (Ki = 0.882-1.29 µM) were almost equivalent regardless of the enzyme sources used, whereas the inhibitory potency of CBD (Ki > = 0.954-9.88 µM) varied depending on the enzyme sources and substrates used. Δ⁹-THC inhibited both S-warfarin 7-hydroxylase and diclofenac 4'-hydroxylase activities of HLMs and rCYP2C9 in a mixed manner. CBD and CBN competitively inhibited the activities of HLMs and rCYP2C9, with the only notable difference being that CBD and CBN exhibited mixed-type inhibitions against diclofenac 4'-hydroxylation and S-warfarin 7-hydroxylation, respectively, by rCYP2C9. None of Δ⁹-THC, CBD, and CBN exerted metabolism-dependent inhibition. These results indicated that the three major phytocannabinoids but not PAHs contained in marijuana smoke potently inhibited CYP2C9 activity and that these cannabinoidscan be characterized as direct inhibitors for CYP2C9.	22.166.891		22166891	Hokuriku University				published	1	1	Published report
http://repo.napdi.org/NPDI-l0yevQ	102	Cannabis	CB2 and TRPV1 receptors mediate cannabinoid actions on MDR1 expression in multidrug resistant cells	PMID: 22814029	BACKGROUND: Cannabis is the most widely used illicit drug in the world that is often used by cancer patients in combination with conventional anticancer drugs. Multidrug resistance (MDR) is a major obstacle in the treatment of cancer. An extensively characterized mechanism of MDR involves overexpression of P-glycoprotein (P-gp), which reduces the cellular accumulation of cytotoxic drugs in tumor cells. METHODS: Here we examined the role of cannabinoid receptors and transient receptor potential vanilloid type 1 (TRPV(1)) receptors in the effects of plant-derived cannabinoids on MDR1 mRNA expression in MDR CEM/VLB(100) cells which overexpress P-gp due to MDR1 gene amplification. RESULTS: We showed that both cannabidiol (CBD) and Δ(9)-tetrahydrocannabinol (Δ(9)-THC) (10 μM) transiently induced the MDR1 transcript in P-gp overexpressing cells at 4 but not 8 or 48 h incubation durations. CBD and THC also concomitantly increased P-gp activity as measured by reduced accumulation of the P-gp substrate Rhodamine 123 in these cells with a maximal inhibitory effect observed at 4 h that slowly diminished by 48 h. CEM/VLB(100) cell lines were shown to express CB(2) and TRPV(1) receptors. Δ(9)-THC effects on MDR1 expression were mediated by CB(2) receptors. The effects of CBD were not mediated by either CB(2) or TRPV(1) receptors alone, however, required activation of both these receptors to modulate MDR1 mRNA expression. CONCLUSION: This is the first evidence that CB(2) and TRPV(1) receptors cooperate to modulate MDR1 expression.	22.814.029		School of Medical Sciences (Pharmacology) and Bosch Institute	The University of Sydney				published	1	1	Published report
http://repo.napdi.org/NPDI-yvZDKA	2	Green tea	Green tea (Camellia sinensis) extract does not alter cytochrome P450 3A4 or 2D6 activity in healthy volunteers.	PMID:15319329	Green tea extract is a widely used dietary supplement. The objective of this study was to assess the influence of a decaffeinated green tea (DGT; Camellia sinensis) extract on the activity of the drug-metabolizing enzymes cytochrome P-450 2D6 and 3A4. Probe drugs dextromethorphan (30 mg, CYP2D6 activity) and alprazolam (ALPZ; 2 mg, CYP3A4 activity) were administered orally to healthy volunteers (n = 11) at baseline, and again after treatment with four DGT capsules/day for 14 days. Each DGT capsule contained 211 +/- 25 mg of green tea catechins and <1 mg of caffeine. Dextromethorphan metabolic ratios (DMRs) and alprazolam pharmacokinetics were determined at baseline and after DGT treatment. There were no significant differences in ALPZ pharmacokinetics at baseline and after DGT treatment (all P values >/= 0.05; maximum concentration in plasma, 33 +/- 8 versus 34 +/- 13 ng/ml; time to reach maximum concentration in plasma, 1.4 +/- 1.2 versus 1.4 +/- 1.2 h; area under the plasma concentration versus time curve, 480 +/- 119 versus 510 +/- 107 h. ng. ml(-1); half-life of elimination, 12.3 +/- 1.7 versus 13.1 +/- 3.4 h). The DMR was 0.053 +/- 0.045 at baseline and 0.041 +/- 0.032 after DGT supplementation (P > 0.05). The plasma concentration of the green tea flavonoid, (-)-epigallocatechin gallate, reached 1.3 +/- 1.8 microM 2 h after DGT treatment. Our results indicate that DGT is unlikely to alter the disposition of medications primarily dependent on the CYP2D6 or CYP3A4 pathways of metabolism.	15.319.329		N/A	Medical University of South Carolina General Clinical Research Center			This study is reported in the literature. The data was entered by RB and reviewed by JS.	published	1	1	Published report
http://repo.napdi.org/NPDI-paKXvg	796	Aloe vera	Aloe vera leaf extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-aloe-vera-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-rmRb0A	72	Goldenseal	Effects of berberine on the blood concentration of cyclosporin A in renal transplanted recipients: clinical and pharmacokinetic study	PMID: 16133554	Objective: To study the effects of berberine (BBR) on the blood concentration and pharmacokinetics of cyclosporin A (CsA) in renal-transplant recipients. Methods: In a randomized and controlled clinical trial, 52 renal-transplant recipients were treated with CsA and 0.2 g BBR three times daily for 3 months, while another 52 subjects received CsA without BBR co-administration. Blood trough concentration of CsA and biochemistry indexes for hepatic and renal functions were determined. For the pharmacokinetic study, six renal transplant recipients were included with a 3-mg/kg dosage of CsA twice daily before and after oral co- administration of 0.2 g BBR three times daily for 12 days. Results: The trough blood concentrations and the ratios of concentration/dose of CsA in the BBR-treated group increased by 88.9% and 98.4%, respectively, compared with those at baseline (P<0.05). As for the BBR-free group, they rose by 64.5% and 69.4%, respectively, relative to those at baseline (P<0.01). Nevertheless, the final blood concentrations and the ratios of concentration/dose of CsA in BBR-treated patients were still 29.3% and 27.8%, respectively, higher than those in BBR-free patients (P<0.05). No significant effects on liver or renal functions were observed under coadministration of BBR. After co-administra- tion of BBR in six patients for 12 days, the mean AUC of CsA was increased by 34.5% (P<0.05). The mean time taken to reach the peak blood concentration (tmax) and the mean half-life (t1/2) of CsA were increased by 1.7 h and 2.7 h, respectively (P<0.05). The average percentage increases in the steady-state drug con- centration (Css) and minimum blood concentration (Cmin) were 34.5% and 88.3%, respectively (P<0.05). In addition, the average percentage decrease in CL/F was 40.4% (P<0.05) and the peak-to-through fluctuation index was significantly reduced (P<0.01). Conclusion: The BBR can markedly elevate the blood concentration of CsA in renal-transplant recipients in both clinical and pharmacokinetic studies. This combination may allow a reduction of the CsA dosage. The mechanism for this interaction is most likely explained by inhibition of CYP3A4 by BBR in the liver and/or small intestine.	16.133.554		Wuhan General Hospita	Wuhan General Hospita				published	1	1	Published report
http://repo.napdi.org/NPDI-j3Ja2Q	823	Wheat grass	Wheat grass grains extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-AHR-wheat-grass-1	Natural Center for Natural Products Research			PXR fold activation results not available	published	1	1	Published report
http://repo.napdi.org/NPDI-Y8SO6A	819	Yohimbe	Yohimbe bark extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-yohimbe-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-diarHw	813	Goldenseal	Goldenseal root extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-goldenseal-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-K89fCg	15	Green tea	Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E.	PMID:11205489	Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E. There are a total of 8 experiments, 1 each for EGCG capsules at 4 dose levels, and 1 each for Polyphenon E capsules at 4 dose levels. The PK results for the EGCG compound is recorded for the four experiments that used EGCG capsules but not the 4 experiments using Polyphenon E capsules because the there were not significant differences at any of the dose levels. This is true for both unconjugated and total EGCG. The EGC and EC results were only available for the 4 Polyphenon E experiments and these are recorded.	11.205.489		T4	Various academic, government, and commercial entities			This is a study reported in the literature. The data was entered by RB and reviewed by JY (entries not completed yet).	published	1	1	Published report
http://repo.napdi.org/NPDI-Tq41aQ	77	Goldenseal	In Vivo and in Vitro Study on Drug-Drug Interaction of Lovastatin and Berberine from Pharmacokinetic and HepG2 Cell Metabolism Studies	PMID: 27070564	Background: We assumed that the pharmacokinetics of lovastatin could be changed by the induction effect of berberine. Methods: An UPLC-MS/MS method was developed and validated for the pharmacokinetics tudy of lovastatin to investigate the in vivo drug-drug interactions between lovastatin and berberine. SD male rats were random divided into lovastatin group and berberine induced prior to lovastatin group for the in vivo pharmacokinetic studies. Meanwhile HepG2 cells were induced by berberine for three days to study the metabolism of lovastatin. Results: The AUC (p < 0.01) and Cmax (p < 0.01) could be significantly decreased in the berberine-induced groupin vivo, and the metabolic activity of HepG2 cell ccould be increased by berberine induction in vitro. The metabolism parameters of lovastatin such as CL, Vmax and Km were increased after the induction of berberine. From the pharmacokinetic study of lovastatin induced with berberine, we obtained pharmacokinetic parameters which are compliance with the metabolic parameters of lovastatin in HepG2 cells with berberine induction in vitro. Conclusions: From the in vivo pharmacokinetics study and the HepG2 cell metabolism study in vitro, berberine could be an inducer for the metabolism of lovastatin according to our previous research on berberine induction effects on HepG2 cells, which may be relevant to the fact that berberine possesses induction effects through the CYP 450 3A4 enzyme.	27.070.564		China Academy of Chinese Medical Sciences	Guang’anmen Hospital				published	1	1	Published report
http://repo.napdi.org/NPDI-ftEv0g	73	Goldenseal	In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4 phenotypes	PMID: 15900287	Objectives— Phytochemical-mediated modulation of cytochrome P-450 activity may underlie many herb-drug interactions. Single time-point, phenotypic metabolic ratios were used to determine whether long-term supplementation of goldenseal (Hydrastis canadensis), black cohosh (Cimicifuga racemosa), kava kava (Piper methysticum), or valerian (Valeriana officinalis) extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4/5 activity. Methods— Twelve healthy volunteers (6 females) were randomly assigned to receive goldenseal, black cohosh, kava kava, or valerian for 28 days. For each subject, a 30-day washout period was interposed between each supplementation phase. Probe drug cocktails of midazolam and caffeine, followed 24 hours later by chlorzoxazone and debrisoquine were administered before (baseline) and at the end of supplementation. Pre- and post-supplementation phenotypic trait measurements were determined for CYP3A4/5, CYP1A2, CYP2E1, and CYP2D6 using 1-hydroxymidazolam/midazolam serum ratios (1-hour sample), paraxanthine/caffeine serum ratios (6-hour sample), 6- hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour sample), and debrisoquine urinary recovery ratios (8-hour collection), respectively. The content of purported “active” phytochemicals was determined for each supplement. Results— Comparisons of pre- and post-supplementation phenotypic ratio means revealed significant inhibition (~40%) of CYP2D6 (difference = −0.228; 95% CI = −0.268 to −0.188) and CYP3A4/5 (difference = −1.501; 95% CI = −1.840 to −1.163) activity for goldenseal. Kava produced significant reductions (~40%) in CYP2E1 only (difference = −0.192; 95% CI = −0.325 to −0.060). Black cohosh also exhibited statistically significant inhibition of CYP2D6 (difference = −0.046; 95% CI = −0.085 to −0.007), but the magnitude of the effect (~7%) did not appear clinically relevant. No significant changes in phenotypic ratios were observed for valerian. Conclusions— Botanical supplements containing goldenseal strongly inhibited CYP2D6 and CYP3A4/5 activity in vivo, while kava inhibited CYP2E1 and black cohosh weakly inhibited CYP2D6. Accordingly, serious adverse interactions may result from the concomitant ingestion of goldenseal supplements and drugs that are CYP2D6 and CYP3A4/5 substrates. Kava kava and black cohosh may interact with CYP2E1 and CYP2D6 substrates, respectively. Valerian appears less likely to produce CYP-mediated herb-drug interactions.	15.900.287		University of Arkansas for Medical Sciences,	Department of Pharmaceutical Sciences				published	1	1	Published report
http://repo.napdi.org/NPDI-kpUP9w	806	Turmeric	Turmeric rhizome extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-turmeric-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-FfN_4A	56	Kratom	Evaluation of the Effects of Mitragyna speciosa Alkaloid Extract on Cytochrome P450 Enzymes Using a High Throughput Assay		The extract from Mitragyna speciosa has been widely used as an opium substitute, mainly due to its morphine-like pharmacological effects. This study investigated the effects of M. speciosa alkaloid extract (MSE) on human recombinant cytochrome P450 (CYP) enzyme activities using a modified Crespi method. As compared with the liquid chromatography-mass spectrometry method, this method has shown to be a fast and cost- effective way to perform CYP inhibition studies. The results indicated that MSE has the most potent inhibitory effect on CYP3A4 and CYP2D6, with apparent half-maximal inhibitory concentration (IC50) values of 0.78 μg/mL and 0.636 μg/mL, respectively. In addition, moderate inhibition was observed for CYP1A2, with an IC50 of 39 μg/mL, and weak inhibition was detected for CYP2C19. The IC50 of CYP2C19 could not be determined, however, because inhibition was <50%. Competitive inhibition was found for the MSE-treated CYP2D6 inhibition assay, whereas non-competitive inhibition was shown in inhibition assays using CYP3A4, CYP1A2 and CYP2C19. Quinidine (CYP2D6), ketoconazole (CYP3A4), tranylcypromine (CYP2C19) and furafylline (CYP1A2) were used as positive controls throughout the experiments. This study shows that MSE may contribute to an herb-drug interaction if administered concomitantly with drugs that are substrates for CYP3A4, CYP2D6 and CYP1A2.	21.876.481	362645751	Department of Pharmacology, Faculty of Medicine, University of Malaya; Aurigene Discovery Technologies	Department of Pharmacology, Faculty of Medicine, University of Malaya; Aurigene Discovery Technologies				published	1	1	Published report
http://repo.napdi.org/NPDI-BUBqZg	261	Ceylon cinnamon	Mechanisms of Herb-Drug Interactions Involving Cinnamon and CYP2A6: Focus on Time-Dependent Inhibition by Cinnamaldehyde and 2-Methoxycinnamaldehyde		Information is scarce regarding pharmacokinetic-based herb-drug interactions (HDI) with trans-cinnamaldehyde (CA) and 2-methoxycinnamaldehyde (MCA), components of cinnamon. Given the presence of cinnamon in food and herbal treatments for various diseases, HDIs involving the CYP2A6 substrates nicotine and letrozole with MCA (K_S = 1.58 µM; Hill slope = 1.16) and CA were investigated. The time-dependent inhibition (TDI) by MCA and CA of CYP2A6-mediated nicotine metabolism is a complex process involving multiple mechanisms. Molecular dynamic simulations showed that CYP2A6's active site accommodates two dynamic ligands. The preferred binding orientations for MCA and CA were consistent with the observed metabolism: epoxidation, O-demethylation, and aromatic hydroxylation of MCA and cinnamic acid formation from CA. The percent remaining activity plots for TDI by MCA and CA were curved, and they were analyzed with a numerical method using models of varying complexity. The best-fit models support multiple inactivator binding, inhibitor depletion, and partial inactivation. Deconvoluted mass spectra indicated that MCA and CA modified CYP2A6 apoprotein with mass additions of 156.79 (142.54-171.04) and 132.67 (123.37-141.98), respectively, and it was unaffected by glutathione. Heme degradation was observed in the presence of MCA (48.5% ± 13.4% loss; detected by liquid chromatography-tandem mass spectrometry). In the absence of clinical data, HDI predictions were made for nicotine and letrozole using inhibition parameters from the best-fit TDI models and parameters scaled from rats. Predicted area under the concentration-time curve fold changes were 4.29 (CA-nicotine), 4.92 (CA-letrozole), 4.35 (MCA-nicotine), and 5.00 (MCA-letrozole). These findings suggest that extensive exposure to cinnamon (corresponding to ≈ 275 mg CA) would lead to noteworthy interactions. SIGNIFICANCE STATEMENT: Human exposure to cinnamon is common because of its presence in food and cinnamon-based herbal treatments. Little is known about the risk for cinnamaldehyde and methoxycinnamaldehyde, two components of cinnamon, to interact with drugs that are eliminated by CYP2A6-mediated metabolism. The interactions with CYP2A6 are complex, involving multiple-ligand binding, time-dependent inhibition of nicotine metabolism, heme degradation, and apoprotein modification. An herb-drug interaction prediction suggests that extensive exposure to cinnamon would lead to noteworthy interactions with nicotine.	32.788.161		PUO-2	School of Pharmacy, Pacific University Oregon				published	1	1	Published report
http://repo.napdi.org/NPDI-lY9NZQ	189	Cannabis	Cannabidiol induces expression of human cytochrome P450 1A1 that is possibly mediated through aryl hydrocarbon receptor signaling in HepG2 cells		Aims: We herein investigated the inducibility of cytochrome P450 1A1 (CYP1A1) by Δ⁹-tetrahydrocannabinol, cannabidiol (CBD), and cannabinol, three major phytocannabinoids, using human hepatoma HepG2 cells. Main methods: The expression of CYP1A1 and the aryl hydrocarbon receptor (AhR) was measured by a quantitative real-time polymerase chain reaction and/or Western blotting. Key findings: Δ⁹-Tetrahydrocannabinol and CBD concentration-dependently induced the expression of CYP1A1 mRNA, whereas cannabinol showed little or no induction. Among the phytocannabinoids tested, CBD was the most potent inducer of CYP1A1 expression. The induction of CYP1A1 expression by CBD was significantly attenuated by the knockdown of AhR expression with AhR small interfering RNAs. The role of protein tyrosine kinases (PTKs) in the CBD-mediated induction of CYP1A1 was then examined using herbimycin A, a PTK inhibitor. The upregulation of CYP1A1 by CBD was significantly suppressed by herbimycin A as was the induction by omeprazole but not 3-methylcholanthrene. The inducibility of CYP1A1 by CBD-related compounds was examined to clarify the structural requirements for CBD-mediated CYP1A1 induction. Olivetol, which corresponds to the pentylresorcinol moiety of CBD, significantly induced the expression of CYP1A1, whereas d-limonene, CBD-2′- monomethyl ether, and CBD-2′,6′-dimethyl ether did not. Significance: These results showed that CBDmay have induced human CYP1A1 expression through the activation of PTK-dependent AhR signaling, in which two phenolic hydroxyl groups in the pentylresorcinol moiety of CBD may play structurally important roles.	26.187.180		Shinshu	Shinshu University Hospital				published	1	1	Published report
http://repo.napdi.org/NPDI-S1YNJQ	13	Green tea	Inhibitory effects of commonly used herbal extracts on UGT1A1 enzyme activity.	PMID:20666626	A panel of nine commonly used herbal supplements were screened for their potential to inhibit UGT1A1 activity using human liver microsomes. The result of green tea constituient epigallocatechin gallate (EGCG) was entered. Based on the in vitro findings, inhibition of UGT1A1 by EGCG is plausible, particularly in the intestine where higher extract concentrations are anticipated. Further clinical studies are warranted.	20.666.626		University of Florida	Department of Pharmacotherapy and Translational Reserach, University of Florida			This is a study reported in the literature. The data was entered by JY and reviewed by JS.	published	1	1	Published report
http://repo.napdi.org/NPDI-BvR0Pw	91	Cannabis	Pharmacological Effects of Cannabinoids on the Caco-2 Cell Culture Model of Intestinal Permeability	PMID: 20592049	Activation of cannabinoid receptors decreases emesis, inflammation, gastric acid secretion, and intestinal motility. However, the effects of cannabinoids on intestinal permeability have not yet been established. The aim of the present study is to examine the effects of cannabinoids on intestinal permeability in an in vitro model. Caco-2 cells were grown until fully confluent on inserts in 12-well plates. Transepithelial electrical resistance (TEER) measurements were made as a measure of permeability. EDTA (50 μM) was applied to reversibly increase permeability (reduce TEER). The effects of cannabinoids on permeability in combination with EDTA, or alone, were assessed. Potential target sites of action were investigated using antagonists of the cannabinoid (CB)(1) receptor, CB(2) receptor, transient receptor potential vanilloid subtype 1 (TRPV1), peroxisome proliferator-activated receptor (PPAR)γ, PPARα, and a proposed cannabinoid receptor. When applied to the apical or basolateral membrane of Caco-2 cells, Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) enhanced the speed of recovery of EDTA-induced increased permeability. This effect was sensitive to cannabinoid CB(1) receptor antagonism only. Apical application of endocannabinoids caused increased permeability, sensitive to cannabinoid CB(1) receptor antagonism. By contrast, when endocannabinoids were applied basolaterally, they enhanced the recovery of EDTA-induced increased permeability, and this involved additional activation of TRPV1. All cannabinoids tested increased the mRNA of the tight junction protein zona occludens-1, but only endocannabinoids also decreased the mRNA of claudin-1. These findings suggest that endocannabinoids may play a role in modulating intestinal permeability and that plant-derived cannabinoids, such as THC and CBD, may have therapeutic potential in conditions associated with abnormally permeable intestinal epithelium.	20.592.049		University of Nottingham	Royal Derby Hospital				published	1	1	Published report
http://repo.napdi.org/NPDI-l4wD_A	165		Inhibition of CYP enzymes by glycycoumarin		The potential of licorice dietary supplements to interact with drug metabolism was evaluated by testing extracts of three botanically identified licorice species (Glycyrrhiza glabra L., Glycyrrhiza uralensis Fish. ex DC. and Glycyrrhiza inflata Batalin) and 14 isolated licorice compounds for inhibition of 9 cytochrome P450 enzymes using a UHPLC-MS/MS cocktail assay. G. glabra showed moderate inhibitory effects against CYP2B6, CYP2C8, CYP2C9, and CYP2C19, and weak inhibition against CYP3A4 (testosterone). In contrast, G. uralensis strongly inhibited CYP2B6 and moderately inhibited CYP2C8, CYP2C9 and CYP2C19, and G. inflata strongly inhibited CYP2C enzymes and moderately inhibited CYP1A2, CYP2B6, CYP2D6, and CYP3A4 (midazolam). The licorice compounds isoliquiritigenin, licoricidin, licochalcone A, 18β-glycyrrhetinic acid, and glycycoumarin inhibited one or more members of the CYP2C family of enzymes. Glycycoumarin and licochalcone A inhibited CYP1A2, but only glycycoumarin inhibited CYP2B6. Isoliquiritigenin, glabridin and licoricidin competitively inhibited CYP3A4, while licochalcone A (specific to G. inflata roots) was a mechanism-based inhibitor. The three licorice species commonly used in botanical dietary supplements have varying potential for drug-botanical interactions as inhibitors of cytochrome P450 isoforms. Each species of licorice displays a unique profile of constituents with potential for drug interactions.	28.774.812		UIC	UIC	22/03/2017 12:00 AM	30/07/2017 12:00 AM		published	1	1	Published report
http://repo.napdi.org/NPDI-6PgT2w	152	Kratom	Kratom Metabolomics		Metabolomics analysis of 51 kratom prdocuts			UNCG	University of North Carolina - Greensboro				published	3	3	Unpublished data submitted through a NaPDI form
http://repo.napdi.org/NPDI-Szj4NQ	5	Green tea	Green tea ingestion greatly reduces plasma concentrations of nadolol in healthy subjects.	PMID:24419562	This study aimed to evaluate the effects of green tea on the pharmacokinetics and pharmacodynamics of the β-blocker nadolol. The study includes a trasport experiment using cells stably expressing the organic anion–transporting polypeptides OATP1A2 and OATP2B1.	24.419.562		T3	Multiple international academic organizations			This is a study reported in the literature. The data was entered by RB and reviewed by JY.	published	1	1	Published report
http://repo.napdi.org/NPDI-TvFD4g	822	Elderberry	Elderberry fruit extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-elderberry-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-dBrDOg	112	Goldenseal	Human MDR1 and MRP1 Recognize Berberine as Their Transport Substrate	PMID: 17213652	To examine whether human ATP-binding cassette (ABC) transporters play a role in the detoxification of plant alkaloid berberine, we investigated berberine transport using multidrug resistance protein1 (MDR1) and multidrug resistance-associated protein1 (MRP1). Cells expressing MDR1 or MRP1 accumulated less berberine. Berberine accumulation depended on the cellular ATP level, and was reversed by typical inhibitors of MDR1, suggesting that human MDR1 and MRP1 directly efflux berberine as their substrate.	17.213.652		Research Institute for Sustainable Humanosphere	Laboratory of Plant Gene Expression				published	1	1	Published report
http://repo.napdi.org/NPDI-uO_CeA	96	Goldenseal	Inhibition of P-Glycoprotein by HIV Protease Inhibitors Increases Intracellular Accumulation of Berberine in Murine and Human Macrophages	PMID: 23372711	Background: HIV protease inhibitor (PI)-induced inflammatory response in macrophages is a major risk factor for cardiovascular diseases. We have previously reported that berberine (BBR), a traditional herbal medicine, prevents HIV PI- induced inflammatory response through inhibiting endoplasmic reticulum (ER) stress in macrophages. We also found that HIV PIs significantly increased the intracellular concentrations of BBR in macrophages. However, the underlying mechanisms of HIV PI-induced BBR accumulation are unknown. This study examined the role of P-glycoprotein (P-gp) in HIV PI-mediated accumulation of BBR in macrophages. Methodology and Principal Findings: Cultured mouse RAW264.7 macrophages, human THP-1-derived macrophages, Wild type MDCK (MDCK/WT) and human P-gp transfected (MDCK/P-gp) cells were used in this study. The intracellular concentration of BBR was determined by HPLC. The activity of P-gp was assessed by measuring digoxin and rhodamine 123 (Rh123) efflux. The interaction between P-gp and BBR or HIV PIs was predicated by Glide docking using Schrodinger program. The results indicate that P-gp contributed to the efflux of BBR in macrophages. HIV PIs significantly increased BBR concentrations in macrophages; however, BBR did not alter cellular HIV PI concentrations. Although HIV PIs did not affect P- gp expression, P-gp transport activities were significantly inhibited in HIV PI-treated macrophages. Furthermore, the molecular docking study suggests that both HIV PIs and BBR fit the binding pocket of P-gp, and HIV PIs may compete with BBR to bind P-gp. Conclusion and Significance: HIV PIs increase the concentration of BBR by modulating the transport activity of P-gp in macrophages. Understanding the cellular mechanisms of potential drug-drug interactions is critical prior to applying successful combinational therapy in the clinic.	23.372.711		Virginia Commonwealth University	Department of Microbiology and Immunology				published	1	1	Published report
http://repo.napdi.org/NPDI-XbFHUg	818	Oregano	Oregano leaf extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-oregano-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-ieYYdA	107	Cannabis	Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6.	PMID: 21821735	Δ(9)-Tetrahydrocannabinol, cannabidiol (CBD), and cannabinol are the three major cannabinoids contained in marijuana, which are devoid of nitrogen atoms in their structures. In this study, we investigated the inhibitory effects of the major phytocannabinoids on the catalytic activity of human CYP2D6. These major cannabinoids inhibited the 3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4-methylcoumarin (AMMC) and dextromethorphan O-demethylase activities of recombinant CYP2D6 and pooled human liver microsomes in a concentration-dependent manner (IC(50) = 4.01-24.9 μM), indicating the strongest inhibitory potency of CBD. However, these cannabinoids showed no or weak metabolism-dependent inhibition. CBD competitively inhibited the CYP2D6 activities with the apparent K(i) values of 1.16 to 2.69 μM. To clarify the structural requirement for CBD-mediated CYP2D6 inhibition, effects of CBD-related compounds on the AMMC O-demethylase activity of recombinant CYP2D6 were examined. Olivetol (IC(50) = 7.21 μM) inhibited CYP2D6 activity as potently as CBD did (IC(50) = 6.52 μM), whereas d-limonene did not show any inhibitory effect. Pentylbenzene failed to inhibit CYP2D6 activity. Furthermore, neither monomethyl nor dimethyl ethers of CBD inhibited the activity. Cannabidivarin having a propyl side chain inhibited CYP2D6 activity; its inhibitory effect (IC(50) = 10.2 μM) was less potent than that of CBD. On the other hand, orcinol and resorcinol showed lack of inhibition. The inhibitory effect of CBD on CYP2D6 activity was more potent than those of 16 compounds without nitrogen atoms tested, such as progesterone. These results indicated that CBD caused potent direct CYP2D6 inhibition, in which two phenolic hydroxyl groups and the pentyl side chain of CBD may play important roles.	21.821.735		Faculty of Pharmaceutical Sciences	Hokuriku University				published	1	1	Published report
http://repo.napdi.org/NPDI-fo-66g	820	Black pepper	Black pepper fruit extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-black-pepper-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-47DSLg	108	Goldenseal	Effects of Herbal Products and their Constituents on Human Cytochrome P4502E1 Activity	PMID: 17658211	Ethanolic extracts from fresh Echinacea purpurea and Spilanthes acmella and dried Hydrastis canadensis were examined with regard to their ability to inhibit cytochrome P4502E1 mediated oxidation of p-nitrophenol in vitro. In addition, individual constituents of these extracts, including alkylamides from E. purpurea and S. acmella, caffeic acid derivatives from E. purpurea, and several of the major alkaloids from H. canadensis, were tested for inhibition using the same assay. H. canadensis (goldenseal) was a strong inhibitor of the P4502E1, and the inhibition appeared to be related to the presence of the alkaloids berberine, hydrastine and canadine in the extract. These compounds inhibited 2E1 with KI values ranging from 2.8 μM for hydrastine to 18 μM for berberine. The alkylamides present in E. purpurea and S. acmella also showed significant inhibition at concentrations as low as 25 μM, whereas the caffeic acid derivatives had no effect. Commercial green tea preparations, along with four of the individual tea catechins, were also examined and were found to have no effect on the activity of P4502E1.	17.658.211		The University of North Carolina at Greensboro	Department of Chemistry and Biochemistry				published	1	1	Published report
http://repo.napdi.org/NPDI-8lgFiA	65	Cannabis	Interaction between Marihuana and Ethanol: Effects on Psychomotor Performance	PMID: 2837105	This is a report of the results of a placebo-controlled study in which the effects of the interaction between ethanol and marihuana on drug plasmaconcentrations, subjectiveratingsof intoxication, heart rate acceleration, and psychomotor performance were investigated. Six healthy, male, paid volunteers, moderate users of ethanol and marihuana, participated in th estudy. Ethanol(0.42g/kg,0.85 g/kg, or placebo)was administered over a 30-min interval. Fifteen minutes later the subjects smoked, in their customary manner, NIDA cigarettes containing 2.4% or 0.0004% (placebo) δ-6-9-tetrahydrocannabinol (THC). Each subject was tested in a single-blind, latin-square crossover design with the following six conditions: placebo ethanol/ placebo marihuana; low dose ethanol/placebo marihuana; high dose ethanollplacebo marihuana; placebo ethanol/manhuana; low dose ethand/marihuana; and high dose ethand/marihuana. The variables measured in the study were: (a) subjective rating of ethanol and/or marihuana intoxication; (b) heart rate; (c) accuracy and latency of response in the Simulator Evaluationof Drug Impairment (SEDI) task; (d) blood ethanol concentration by gas chromatography; and (e) plasma concentration of THC by radioimmunoassay. The results indicate that the decrements due to ethanol in performance of skills necessary to drive an automobile were significantly enhanced by marihuana in an additive and perhaps synergistic manner. The administration of ethanol prior to marihuana smoking did not produce significant effects on the subjective rating of “high,” heart rate acceleration, or THC plasma concentration.	2.837.105		Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill	Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill				published	1	1	Published report
http://repo.napdi.org/NPDI-UaGLOg	85	Cannabis	Characterization of P-glycoprotein Inhibition by Major Cannabinoids from Marijuana	PMID: 16439618	The ATP-dependent drug efflux transporter P-glycoprotein (P-gp) plays a significant role in the absorption and disposition of many compounds. The purpose of this study was to investigate the possible interaction of P-gp with each of four major marijuana constituents: Delta(9)-tetrahydrocannabinol (THC), 11-nor-Delta(9)-tetrahydrocannabinol-carboxylic acid (THC-COOH), cannabinol (CBN), and cannabidiol (CBD). The results of a P-gp ATPase activity screen showed that THC-COOH, CBN, THC, and CBD all stimulated P-gp ATPase activity with a Michaelis-Menten parameter (V(max)/K(m)) value of 1.3, 0.7, 0.1, and 0.05, respectively. Furthermore, CBD showed a concentration-dependent inhibitory effect on verapamil-stimulated ATPase activity with an IC(50) value of 39.6 microM, whereas all other tested cannabinoids did not display appreciable inhibitory effects. Thus, the inhibitory effects of CBD on P-gp transport were further studied. At concentrations ranging from 5 to 100 microM, CBD robustly enhanced the intracellular accumulation of known P-gp substrates rhodamine 123 and doxorubicin in a concentration-dependent manner in Caco-2 and LLC-PK1/MDR1 cells. An IC(50) value of 8.44 microM was obtained for inhibition of P-gp function in LLC-PK1/MDR1 cells as determined by flow cytometry using rhodamine 123 as a fluorescence probe. Following exposure to 30 microM CBD, the apparent permeability coefficient of rhodamine 123 across Caco-2 and rat brain microvessel endothelial cell monolayers was increased to 2.2- and 2.6-fold in the apical-to-basolateral direction but decreased to 0.69- and 0.47-fold in the basolateral-to-apical direction, respectively. These findings indicate that CBD significantly inhibits P-gp-mediated drug transport, suggesting CBD could potentially influence the absorption and disposition of other coadministered compounds that are P-gp substrates.	16.439.618		Medical University of South Carolina	Medical University of South Carolina				published	1	1	Published report
http://repo.napdi.org/NPDI-N-qGfA	164		Inhibition of CYP enzymes by glabridin		The potential of licorice dietary supplements to interact with drug metabolism was evaluated by testing extracts of three botanically identified licorice species (Glycyrrhiza glabra L., Glycyrrhiza uralensis Fish. ex DC. and Glycyrrhiza inflata Batalin) and 14 isolated licorice compounds for inhibition of 9 cytochrome P450 enzymes using a UHPLC-MS/MS cocktail assay. G. glabra showed moderate inhibitory effects against CYP2B6, CYP2C8, CYP2C9, and CYP2C19, and weak inhibition against CYP3A4 (testosterone). In contrast, G. uralensis strongly inhibited CYP2B6 and moderately inhibited CYP2C8, CYP2C9 and CYP2C19, and G. inflata strongly inhibited CYP2C enzymes and moderately inhibited CYP1A2, CYP2B6, CYP2D6, and CYP3A4 (midazolam). The licorice compounds isoliquiritigenin, licoricidin, licochalcone A, 18β-glycyrrhetinic acid, and glycycoumarin inhibited one or more members of the CYP2C family of enzymes. Glycycoumarin and licochalcone A inhibited CYP1A2, but only glycycoumarin inhibited CYP2B6. Isoliquiritigenin, glabridin and licoricidin competitively inhibited CYP3A4, while licochalcone A (specific to G. inflata roots) was a mechanism-based inhibitor. The three licorice species commonly used in botanical dietary supplements have varying potential for drug-botanical interactions as inhibitors of cytochrome P450 isoforms. Each species of licorice displays a unique profile of constituents with potential for drug interactions.	28.774.812		UIC	UIC	22/03/2017 12:00 AM	30/07/2017 12:00 AM		published	1	1	Published report
http://repo.napdi.org/NPDI-EngCtg	78	Cannabis	Medicinal Cannabis Does Not Influence the Clinical Pharmacokinetics of Irinotecan and Docetaxel	PMID: 17405893	OBJECTIVE: To date, data regarding the potential of cannabinoids to modulate cytochrome P450 isozyme 3A (CYP3A) activity are contradictory. Recently, a standardized medicinal cannabis product was introduced in The Netherlands. We anticipated an increased use of medicinal cannabis concurrent with anticancer drugs, and undertook a drug-interaction study to evaluate the effect of concomitant medicinal cannabis on the pharmacokinetics of irinotecan and docetaxel, both subject to CYP3A-mediated biotransformation. PATIENTS AND METHODS: Twenty-four cancer patients were treated with i.v. irinotecan (600 mg, n = 12) or docetaxel (180 mg, n = 12), followed 3 weeks later by the same drugs concomitant with medicinal cannabis (200 ml herbal tea, 1 g/l) for 15 consecutive days, starting 12 days before the second treatment. Blood samples were obtained up to 55 hours after dosing and analyzed for irinotecan and its metabolites (SN-38, SN-38G), respectively, or docetaxel. Pharmacokinetic analyses were performed during both treatments. Results are reported as the mean ratio (95% confidence interval [CI]) of the observed pharmacokinetic parameters with and without concomitant medicinal cannabis. RESULTS: Medicinal cannabis administration did not significantly influence exposure to and clearance of irinotecan (1.04; CI, 0.96-1.11 and 0.97; CI, 0.90-1.05, respectively) or docetaxel (1.11; CI, 0.94-1.28 and 0.95; CI, 0.82-1.08, respectively). CONCLUSION: Coadministration of medicinal cannabis, as herbal tea, in cancer patients treated with irinotecan or docetaxel does not significantly influence the plasma pharmacokinetics of these drugs. The evaluated variety of medicinal cannabis can be administered concomitantly with both anticancer agents without dose adjustments.	17.405.893		Erasmus MC University Medical Center Rotterdam	Erasmus MC University Medical Center Rotterdam				published	1	1	Published report
http://repo.napdi.org/NPDI-Em0b2g	133	Goldenseal	Goldenseal Characterization of Material	UNCG-002	CoA for Goldenseal.			UNCG	University of North Carolina - Greensboro			Data entered by EC via a Certificate of Analysis provided by UNCG.	published	3	3	Unpublished data submitted through a NaPDI form
http://repo.napdi.org/NPDI-JcMOhg	100		Inhibitory Mechanisms of Human CYPs by Three Alkaloids Isolated from Traditional Chinese Herbs		The three purified herbal compounds tetrahydropalmatine (Tet), neferine and berberine (Ber) were exploredin vitro for basic inhibition mechanisms towards recombinant human CYP1A2, CYP2D6 and CYP3A4 meta- bolic activities. Phenacetin, dextromethorphan and testosterone, respectively, were used as CYP1A2, CYP2D6 and CYP3A4 substrates, and their metabolites were determined by validated HPLC methodologies. Positive inhibition controls were used. Mechanism-based (irreversible) inhibition was assessed by time-dependent and nicotinamide adenine dinucleotide phosphate-dependent and reversible inhibition by Lineweaver–Burk plot assessments. Inhibition mechanisms were also assessed by computerized interaction prediction by using the Discovery Studio CDOCKER software (Accelrys, San Diego, CA, USA). Tetrahydropalmatine showed a mechanism-based inhibition of both CYP1A2 and CYP2D6, and Ber of CYP2D6. Neferine and Ber both showed a nonmechanistic inhibition of CYP1A2. All compounds showed a similar and significant mechanism-based inhibition of CYP3A4. Tetrahydropalmatine and Ber demonstrated both reversible and irreversible inhi- bition of CYP2D6 and CYP3A4. Tetrahydropalmatine and Ber displayed H-bond and several Pi-bond connec- tions with specific amino acid residues of CYP1A2, CYP2D6 and CYP3A4, giving further knowledge to the identified reversible and irreversible herb–drug interactions. Tetrahydropalmatine and Ber should be considered for herb–drug interactions in clinical therapy until relevant clinical studies are available.	25.640.685		China Academy of Chinese Medical Sciences (CACMS)	Institute of Chinese Materia Medica (ICMM)				published	1	1	Published report
http://repo.napdi.org/NPDI-TcRn0A	804	Indian barberry	Barberry stem extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-AHR-barberry-1	Natural Center for Natural Products Research			PXR fold activation results not available	published	1	1	Published report
http://repo.napdi.org/NPDI-UPO5FQ	803	Shrubby sophora	Chinese Herbal Medicine Sophora Flavescens Activates PXR		Sophora Flavescens (SF) is widely used for treatment of viral hepatitis, cancer, viral myocarditis, gastrointestinal hemorrhage, and skin diseases. SF has been shown to up-regulate CYP3A expression, but this mechanism is not yet known. DPX2 and HepaRG were used to investigate the role of PXR in SF-induced CYP3A expression. A metabolomic approach was used to identify the chemical constituents in SF. N-methylcytisine, a chemical constituent, activated PXR and significantly induced CYP3A4 expression, which was suppressed by sulforaphane, a PXR antagonist. Thus, SF was shown to induce CYP3A expression via PXR activation.	20.736.322		UKMC-1	Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center				published	1	1	Published report
http://repo.napdi.org/NPDI-r7lzqQ	172		Inhibition of UGT2B7 Enzyme Activity in Human and Rat Liver Microsomes by Herbal Constituents		The co-use of conventional drug and herbal medicines may lead to herb-drug interaction via modulation of drug-metabolizing enzymes (DMEs) by herbal constituents. UDP-glucuronosyltransferases (UGTs) catalyzing glucuronidation are the major metabolic enzymes of Phase II DMEs. The in vitro inhibitory effect of several herbal constituents on one of the most important UGT isoforms, UGT2B7, in human liver microsomes (HLM) and rat liver microsomes (RLM) was investigated. Zidovudine (ZDV) was used as the probe substrate to determine UGT2B7 activity. The intrinsic clearance (Vmax/Km) of ZDV in HLM is 1.65 µL/mg/min which is ten times greater than in RLM, which is 0.16 µL/mg/min. Andrographolide, kaempferol-3-rutinoside, mitragynine and zerumbone inhibited ZDV glucuronidation in HLM with IC50 values of 6.18 ± 1.27, 18.56 ± 8.62, 8.11 ± 4.48 and 4.57 ± 0.23 µM, respectively, hence, herb-drug interactions are possible if andrographolide, kaempferol-3-rutinoside, mitragynine and zerumbone are taken together with drugs that are highly metabolized by UGT2B7. Meanwhile, only mitragynine and zerumbone inhibited ZDV glucuronidation in RLM with IC50 values of 51.20 ± 5.95 µM and 8.14 ± 2.12 µM, respectively, indicating a difference between the human and rat microsomal model so caution must be exercised when extrapolating inhibitory metabolic data from rats to humans.	30.347.696	623736757	SAINS	Universiti Sains Malaysia				published	1	1	Published report
http://repo.napdi.org/NPDI-OeAReg	24	Green tea	Identification of Intestinal UDP-Glucuronosyltransferase Inhibitors in Green Tea (Camellia sinensis) Using a Biochemometric Approach: Application to Raloxifene as a Test Drug via In Vitro to In Vivo Extrapolation	DPS-WSU-001	Green tea is a commonly consumed beverage worldwide; thus, identifying green tea-drug interactions would be of high impact. The potential for UDP-glucuronosyltransferase (UGT)-based interactions are relatively understudied, particularly those in the intestine. As with all botanical dietary supplements, green tea is a complex and variable mixture of diverse phytoconstituents. Comprehensive, high-throughput, robust methods are needed to identify candidate precipitants of interactions with drugs. Using a biochemometrics approach that combines chemometrics with established bioassays, intestinal UGT inhibitors in green tea were identified and evaluated for their in vivo interaction potential. Four widely available green teas that were chemically similar to the National Institute of Standards and Technology (NIST) leaf reference material were selected for evaluation as inhibitors of intestinal UGT activity using human intestinal microsomes. Extracts and five fractions (prepared from the original extracts) of each tea were tested (20, 60, 180 µg/mL) using the nonspecific fluorescent substrate 4-methylumbelliferone. Fractions rich in UGT inhibitory constituents were identified via mass spectrometry-based untargeted metabolomics; these fractions were fractionated further and subjected to biochemometric analysis to identify individual UGT inhibitors. The K_i of two of these constituents and the original extract of a representative tea were determined using raloxifene a clinically relevant substrate. The K_i values were applied to a mechanistic static model to evaluate the potential for a green tea-raloxifene interaction in vivo. Effects of the extracts and fractions from all four teas were qualitatively similar, inhibiting intestinal UGT activity in a concentration-dependent manner (by 0 to >95% relative to vehicle control). The UGT inhibitory constituents tended to reside in the more hydrophilic subfractions of the fraction prepared from the representative extract. (−)-Epigallocatechin gallate (EGCG) and (−)-epicatechin gallate (ECG), two abundant catechins contained in green tea, were identified as major UGT inhibitors in these subfractions. K_i values were 2.0 and 0.8-1.0 μM, respectively, which were ~100x lower than concentrations measured in a 240-mL cup of hot tea prepared from the NIST leaf reference material. A biochemometric approach, which combines bioactivity data with chemometric analysis, was successfully applied to green tea for identifying intestinal UGT inhibitors that could precipitate an interaction with raloxifene and other UGT substrates (e.g., raltegravir, ezetimibe, and mycophenolic acid). This comprehensive approach could be applied to other natural products with drug interaction potential.	29.467.215		DPS-WSU	Department of Pharmaceutical Sciences, Washington State University; Department of Chemistry & Biochemistry, University of North Carolina at Greensboro; Department of Population Sciences, City of Hope	01/06/2016 12:00 AM	30/09/2017 12:00 AM	This in vitro study was entered from unpublised data from Dr. Mary Paine's lab. Data was curated by JS and reviewed by JY.	published	2	2	Manuscript prepared or submitted for peer-reviewed publication
http://repo.napdi.org/NPDI-JHPnhA	170	Kratom	The inhibitory effects of mitragynine on P-glycoprotein in vitro		Mitragynine is a major component isolated from Mitragyna speciosa Korth or kratom, a medicinal plant known for its opiate-like and euphoric properties. Multiple toxicity and fatal cases involving mitragynine or kratom have been reported but the underlying causes remain unclear. P-glycoprotein (P-gp) is a multidrug transporter which modulates the pharmacokinetics of xenobiotics and plays a key role in mediating drug-drug interactions. This study investigated the effects of mitragynine on P-gp transport activity, mRNA, and protein expression in Caco-2 cells using molecular docking, bidirectional assay, RT-qPCR, Western blot analysis, and immunocytochemistry techniques, respectively. Molecular docking simulation revealed that mitragynine interacts with important residues at the nucleotide binding domain (NBD) site of the P-gp structure but not with the residues from the substrate binding site. This was consistent with subsequent experimental work as mitragynine exhibited low permeability across the cell monolayer but inhibited digoxin transport at 10 μM, similar to quinidine. The reduction of P-gp activity in vitro was further contributed by the downregulation of mRNA and protein expression of P-gp. In summary, mitragynine is likely a P-gp inhibitor in vitro but not a substrate. Hence, concurrent administration of mitragynine-containing kratom products with psychoactive drugs which are P-gp substrates may lead to clinically significant toxicity. Further clinical study to prove this point is needed.	30.604.191	625786142	SAINS	Universiti Sains Malaysia				published	1	1	Published report
http://repo.napdi.org/NPDI-4xNSSg	55	Kratom	Evaluation of In Vitro Absorption, Distribution, Metabolism, and Excretion (ADME) Properties of Mitragynine, 7-Hydroxymitragynine, and Mitraphylline		Mitragyna speciosa (kratom) is a popular herb in Southeast Asia, which is traditionally used to treat withdrawal symptoms associated with opiate ad- diction. Mitragynine, 7-hydroxymitragynine, and mitraphylline are reported to be the central nervous system active alkaloids which bind to the opiate receptors. Mitraphylline is also present in the bark of Uncaria tomentosa (catʼs claw). Several therapeutic properties have been reported for these compounds but limited information is available on the absorption and distribution properties. This study focuses on evaluating the absorption, distribution, metabolism, and excretion (ADME) properties of these compounds and their effect on major efflux transporter P-glycoprotein, using in vitro methods. Quantitative analysis was performed by the Q‐TOF LC‐MS system. Mitragynine was unstable in simulated gastric fluid with 26% degradation but stable in simulated intestinal fluid. 7-Hydroxymitragynine degraded up to 27% in simulated gastric fluid, which could account for its conversion to mitragynine (23%), while only 6% degradation was seen in simulated intestinal fluid. Mitraphylline was stable in simulated gastric fluid but unstable in simulated intes- tinal fluid (13.6% degradation). Mitragynine and 7-hydroxymitragynine showed moderate permeability across Caco-2 and MDR-MDCK monolayers with no significant efflux. However, mitraphylline was subjected to efflux mediated by P-glycoprotein in both Caco-2 and MDR-MDCK monolayers. Mitragynine was found to be metabolically stable in both human liver microsomes and S9 fractions. In contrast, both 7-hydroxymitragynine and mitraphylline were metabolized by human liver microsomes with half-lives of 24 and 50min, re- spectively. All three compounds exhibited high plasma protein binding (>90%) determined by equilibrium dialysis. Mitragynine and 7-hydroxymitragynine inhibited P-glycoprotein with EC50 values of 18.2 ± 3.6 μM and 32.4 ± 1.9 μM, respectively, determined by the calcein-AM fluorescent assay, while no inhibition was seen with mitra- phylline. These data indicate the possibility of a drug interaction if mitragynine and 7-hydroxy- mitragynine are coadministered with drugs that are P-glycoprotein substrates.	24.841.968	373122811	The University of Mississippi	National Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-XtvOZQ	128	Kratom	Inhibitory effect of mitragynine on human cytochrome P450 enzyme activities		Context: To date, many findings reveal that most of the modern drugs have the ability to interact with herbal drugs. Aims: This study was conducted to determine the inhibitory effects of mitragynine on cytochrome P450 2C9, 2D6 and 3A4 activities. Methods and Material: The in vitro study was conducted using a high-throughput luminescence assay. Statistical Analysis: Statistical analysis was conducted using one-way ANOVA and Dunnett's test with P < 0.05 vs. control. The IC values were calculated using the GraphPad Prism 5 (Version 5.01, GraphPad Software, Inc., USA) Results: Assessment using recombinant enzymes showed that mitragynine gave the strongest inhibitory effect on CYP2D6 with an IC50 value of 0.45±0.33 mM, followed by CYP2C9 and CYP3A4 with IC50 values of 9.70±4.80 and 41.32±6.74 µM respectively. Positive inhibitors appropriate for CYP2C9, CYP2D6, and CYP3A4 which are sulfaphenazole, quinidine and ketoconazole were used respectively. Vmax values of CYP2C9, CYP2D6 and CYP3A4 were 0.0005, 0.01155 and 0.0137 µM luciferin formed/pmol/min respectively. Km values of CYP2C9, CYP2D6, and CYP3A4 were 32.65, 56.01, and 103.30 µM respectively. Mitragynine noncompetitively inhibits CYP2C9 and CYP2D6 activities with the Ki values of 61.48 and 12.86 µM respectively. On the other hand, mitragynine inhibits CYP3A4 competitively with a Ki value of 379.18 µM. Conclusions: The findings of this study reveal that mitragynine might inhibit cytochrome P450 enzyme activities, specifically CYP2D6. Therefore, administration of mitragynine together with herbal or modern drugs which follow the same metabolic pathway may contribute to herb-drug interactions.	24.174.816	2013651136	Centre for Drug Research, Penang	Universiti Sains Malaysia	01/09/2010 12:00 AM	31/07/2011 12:00 AM		published	1	1	Published report
http://repo.napdi.org/NPDI-PSB8Vg	129	Kratom	Evaluation of selected Malaysian medicinal plants on phase I drug metabolizing enzymes, CYP2C9, CYP2D6 and CYP3A4 activities in vitro		This study investigated the effects of selected Malaysian medicinal plant extracts towards human recombinant cytochrome P450 (CYP450) enzyme activities in vitro. Five Malaysian medicinal plants were tested on the three main CYP450 enzyme activities of CYP2C9, CYP2D6 and CYP3A4. The abilities of these extracts to inhibit human cytochrome P450 enzyme activities were analyzed using a luminescent assay. Orthosiphon stamineus showed the most potent inhibitory activity against CYP2C9 with an apparent IC₅₀ value of 77.5±1.1 μg mL^-1, while Andrographis paniculata, Curcuma xanthorrhiza, Eurycoma longifolia and Mitragyna speciosa extracts showed negligible inhibition. On the metabolism mediated by CYP2D6, Mitragyna speciosa showed the most potent inhibitory activities with IC₅₀ values of 3.6±0.1 μg mL^-1, followed by Orthosiphon stamineus, Andrographis paniculata and Curcuma xanthorrhiza with IC₅₀ value of 11.7±1.1, 44.2±4.5 and 215.3±71.6 fig mL^-1, respectively. Andrographis paniculata ethanolic extract gave the lowest IC₅₀ value towards CYP3A4 with an apparent IC₅₀ value of 27.6±3.7 μg mL^-1, followed by Orthosiphon stamineus (78.4±20.3 μg mL^-1), Mitragyna speciosa (142.8±13.8 μg mL^-1) and Curcuma xanthorrhiza (285.3±61.7 μg mL^-1). Sulfaphenazole, quinidine and ketoconazole were used as positive controls for CYP2C9, CYP2D6 and CYP3A4 respectively. The findings suggest that Orthosiphon stamineus, Mitragyna speciosa and Andrographis paniculata may contribute to herb-drug interactions if they are administered concomitantly with drugs metabolized by CYP2C9, CYP2D6 and CYP3A4 respectively.		2010444809	Universiti Sains Malaysia, Penang, Malaysia	Centre for Drug Research	01/05/2009 12:00 AM	28/02/2010 12:00 AM		published	1	1	Published report
http://repo.napdi.org/NPDI-OJbIDw	809	Garcinia	Garcinia cambogia fruit extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-garcinia-cambogia-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-jEZ9Ng	80	Goldenseal	Differential inhibition of CYP1-catalyzed regioselective hydroxylation of estradiol by berberine and its oxidative metabolites	PMID: 26403084	Berberine is a pharmacologically active alkaloid present in widely used medicinal plants, such as Coptis chinensis (Huang-Lian). The hormone estradiol is oxidized by cytochrome P450 (CYP) 1B1 to primarily form the genotoxic metabolite 4-hydroxyestradiol, whereas CYP1A1 and CYP1A2 predominantly generate 2-hydroxyestradiol. To illustrate the effect of berberine on the regioselective oxidation of estradiol, effects of berberine and its metabolites on CYP1 activities were studied. Among CYP1s, CYP1B1.1, 1.3 (L432V), and 1.4 (N453S)-catalyzed 4-hydroxylation were preferentially inhibited by berberine. Differing from the competitive inhibition of CYP1B1.1 and 1.3, N453S substitution in CYP1B1 allowed a non-competitive or mixed-type pattern. An N228T in CYP1B1 highly decreased its activity and preference to 4-hydroxylation. A reverse mutation of T223N in CYP1A2 retained its 2-hydroxylation preference, but enhanced its inhibition susceptibility to berberine. Compared with berberine, metabo- lites demethyleneberberine and thalifendine caused weaker inhibition of CYP1A1 and CYP1B1 activities. Unexpectedly, thalifendine was more potent than berberine in the inhibition of CYP1A2, in which case an enhanced interaction through polar hydrogen-p bond was predicted from the docking analysis. These results demonstrate that berberine preferentially inhibits the estradiol 4-hydroxylation activity of CYP1B1 variants, suggesting that 4-hydroxyestradiol-mediated toxicity might be reduced by berberine, especially in tissues/tumors highly expressing CYP1B1.	26.403.084		Divisions of Basic Chinese Medicine	Divisions of Basic Chinese Medicine				published	1	1	Published report
http://repo.napdi.org/NPDI-FhBdoQ	110	Cannabis	Interaction of drugs of abuse and maintenance treatments with human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2).	PMID: 19887017	Drug interaction with P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) may influence its tissue disposition including blood-brain barrier transport and result in potent drug-drug interactions. The limited data obtained using in-vitro models indicate that methadone, buprenorphine, and cannabinoids may interact with human P-gp; but almost nothing is known about drugs of abuse and BCRP. We used in vitro P-gp and BCRP inhibition flow cytometric assays with hMDR1- and hBCRP-transfected HEK293 cells to test 14 compounds or metabolites frequently involved in addiction, including buprenorphine, norbuprenorphine, methadone, ibogaine, cocaine, cocaethylene, amphetamine, N-methyl-3,4-methylenedioxyamphetamine, 3,4-methylenedioxyamphetamine, nicotine, ketamine, Delta9-tetrahydrocannabinol (THC), naloxone, and morphine. Drugs that in vitro inhibited P-gp or BCRP were tested in hMDR1- and hBCRP-MDCKII bidirectional transport studies. Human P-gp was significantly inhibited in a concentration-dependent manner by norbuprenorphine>buprenorphine>methadone>ibogaine and THC. Similarly, BCRP was inhibited by buprenorphine>norbuprenorphine>ibogaine and THC. None of the other tested compounds inhibited either transporter, even at high concentration (100 microm). Norbuprenorphine (transport efflux ratio approoximately 11) and methadone (transport efflux ratio approoximately 1.9) transport was P-gp-mediated; however, with no significant stereo-selectivity regarding methadone enantiomers. BCRP did not transport any of the tested compounds. However, the clinical significance of the interaction of norbuprenorphine with P-gp remains to be evaluated.	19.887.017		Unite INSERM U705	Universite Paris Descartes				published	1	1	Published report
http://repo.napdi.org/NPDI-Ujn_7A	99	Cannabis	Structural requirements for potent direct inhibition of human cytochrome P450 1A1 by cannabidiol: role of pentylresorcinol moiety.	PMID: 23811569	Our recent work has shown that cannabidiol (CBD) exhibits the most potent direct inhibition of human cytochrome P450 1A1 (CYP1A1) among the CYP enzymes examined. However, the mechanism underlying this CBD inhibition remains to be clarified. Thus, to elucidate the structural requirements for the potent inhibition by CBD, the effects of CBD and its structurally related compounds on CYP1A1 activity were investigated with recombinant human CYP1A1. Olivetol, which corresponds to the pentylresorcinol moiety of CBD, inhibited the 7-ethoxyresorufin O-deethylase activity of CYP1A1; its inhibitory effect (IC50=13.8 µM) was less potent than that of CBD (IC50=0.355 µM). In contrast, d-limonene, which corresponds to the terpene moiety of CBD, only slightly inhibited CYP1A1 activity. CBD-2'-monomethyl ether (CBDM) and CBD-2',6'-dimethyl ether inhibited CYP1A1 activity with IC50 values of 4.07 and 23.0 µM, respectively, indicating that their inhibitory effects attenuated depending on the level of methylation on the free phenolic hydroxyl groups in the pentylresorcinol moiety of CBD. Cannabidivarin inhibited CYP1A1 activity, although its inhibitory potency (IC50=1.85 µM) was lower than that of CBD. The inhibitory effects of Δ(9)-tetrahydrocannabinol and cannabielsoin (IC50s ≈10 µM), which contain a free phenolic hydroxyl group and are structurally constrained, were less potent than that of CBDM, which contains a free phenolic hydroxyl group and is rotatable between pentylresorcinol and terpene moieties. These results suggest that the pentylresorcinol structure in CBD may have structurally important roles in direct CYP1A1 inhibition, although the whole structure of CBD is required for overall inhibition.	23.811.569		Department of Hygienic Chemistry	Hokuriku University				published	1	1	Published report
http://repo.napdi.org/NPDI-EATZ0A	821	Rhodiola	Rhodiola root extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-rhodiola-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI--aO6Bw	94	Goldenseal	Identification of novel dietary phytochemicals inhibiting the efflux transporter breast cancer resistance protein (BCRP/ABCG2)	PMID: 23497885	Breast cancer resistance protein (BCRP/ABCG2) plays an important role in determining the absorption and disposition of consumed xenobiotics including various drugs and dietary phytochemicals and is also one of the prominent efflux transporters involved in multidrug resistance (MDR). In this study, we have investigated the interactions between ABCG2 and 56 naturally-occurring phytochemicals including phenolic acids, flavonoids, triterpenes and other common dietary phytochemicals, as well as two non plant-based compounds (hippuric acid and propyl gallate) using cell- and membrane-based transport inhibition assays. Of the non-flavonoid phytochemicals tested, berberine, celastrol, ellagic acid, limonin, oleanolic acid, propyl gallate, sinapic acid and ursolic acid demonstrated significant inhibition of ABCG2- mediated transport. Chrysoeriol, laricitrin, myricetin 30,40,50-trimethylether, pinocembrin, quercitrin, tamarixetin, tricetin and tricetin 30,40,50-trimethylether were also identified as novel flavonoid ABCG2 inhibitors. The identified inhibitory activity of dietary phytochemicals on ABCG2 provides a framework for further investigation of ABCG2-modulated phytochemical bioavailability, MDR, and possible food– drug interactions.	23.497.885		The University of Auckland	Department of Pharmacology and Clinical Pharmacology				published	1	1	Published report
http://repo.napdi.org/NPDI-euNEwQ	95	Cannabis	Cannabidiol enhances xenobiotic permeability through the human placental barrier by direct inhibition of breast cancer resistance protein: an ex vivo study.	PMID: 23933222	OBJECTIVE: Drugs of abuse affect pregnancy outcomes, however, the mechanisms in which cannabis exerts its effects are not well understood. The aim of this study was to examine the influence of short-term (1-2 hours) exposure to cannabidiol, a major phytocannabinoid, on human placental breast cancer resistance protein function. STUDY DESIGN: The in vitro effect of short-term exposure to cannabidoil on breast cancer resistance protein in BeWo and Jar cells (MCF7/P-gp cells were used for comparison) was tested with mitoxantrone uptake, and nicardipine was used as positive control. The ex vivo perfused cotyledon system was used for testing the effect of cannabidoil on glyburide transport across the placenta. Glyburide (200 ng/mL) was introduced to maternal and fetal compartments through a recirculating 2 hour perfusion, and its transplacental transport was tested with (n = 8) or without (n = 8) cannabidoil. RESULTS: (1) Cannabidoil inhibition of breast cancer resistance protein-dependent mitoxantrone efflux was concentration dependent and of a noncell type specific nature (P < .0001); (2) In the cotyledon perfusion assay, the administration of cannabidoil to the maternal perfusion media increased the female/male ratio of glyburide concentrations (1.3 ± 0.1 vs 0.8 ± 0.1 at 120 minutes of perfusion, P < .001). CONCLUSION: (1) Placental breast cancer resistance protein function is inhibited following even a short-term exposure to cannabidoil; (2) the ex vivo perfusion assay emphasize this effect by increased placental penetration of glyburide to the fetal compartment; and (3) these findings suggest that marijuana consumption enhances placental barrier permeability to xenobiotics and could endanger the developing fetus. Thus, the safety of drugs that are breast cancer resistance protein substrates is questionable during cannabis consumption by pregnant women.	23.933.222		Departments of Clinical Biochemistry and Pharmacology, Obstetrics and Gynecology, Faculty of Health Sciences, School of Medicine	Soroka University Medical Center				published	1	1	Published report
http://repo.napdi.org/NPDI-pHkLHA	122	Goldenseal	An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures	PMID: 10969720	Serial dilutions of 21 commercial ethanolic herbal extracts and tinctures, and 13 related pure plant compounds have been analyzed for their in vitro cytochrome P450 3A4 (CYP3A4) inhibitory capability via a fluorometric microtitre plate assay. Roughly 75% of the commercial products and 50% of the pure compounds showed significant inhibition of CYP3A4 metabolite formation. For each herbal product and pure compound exhibiting dose-dependency, the inhibition values were used to generate median inhibitory concentration (IC50) curves using linear regression. Among the commercial extracts, Hydrastis canadensis (goldenseal), Hypericum perforatum (St. John's wort), and Uncaria tomentosa (cat's claw) had the lowest IC50 values at < 1% full strength, followed by Echinacea angustifolia roots, Trifolium pratense (wild cherry), Matricaria chamomilla (chamomile), and Glycyrrhiza glabra (licorice), which had IC50 values ranging from 1%-2% of full strength. Dillapiol, hypericin, and naringenin had the lowest IC50 values among the pure plant compounds at < 0.5 mM; dillapiol was the most potent inhibitor at 23.3 times the concentration of the positive CYP3A4 inhibitor ketoconazole. Utilizing high-throughput screening methodologies for assessing CYP3A4 inhibition by natural products has important implications for predicting the likelihood of potential herbal-drug interactions, as well as determining candidates for further in-depth analyses.	10.969.720		University of Ottawa	Ottawa-Carieton Institute of Biology				published	1	1	Published report
http://repo.napdi.org/NPDI-Asg_wA	62	Cannabis	Does olanzapine inhibit the psychomimetic effects of Δ9-tetrahydrocannabinol?	PMID: 22596206	Δ⁹-Tetrahydrocannabinol (THC) produces transient psychomimetic effects in healthy volunteers, constituting a pharmacological model for psychosis. The dopaminergic antagonist haloperidol has previously been shown to reduce these effects. This placebo-controlled, cross-over study in 49 healthy, male, mild cannabis users aimed to further explore this model by examining the effect of a single oral dose of olanzapine (with dopaminergic, serotonergic, adrenergic, muscarinergic and histaminergic properties) or two oral doses of diphenhydramine (histamine antagonist) on the effects of intrapulmonarily administered THC. Transient psychomimetic symptoms were seen after THC administration, as measured on the positive and negative syndrome scale (20.6% increase on positive subscale, p<0.001) and the visual analogue scale for psychedelic effects (increase of 10.7 mm on feeling high). Following the combination of THC and olanzapine, the positive subscale increased by only 13.7% and feeling high by only 8.7 mm. This reduction of THC effects on the positive subscale failed to reach statistical significance (p=0.066). However, one-third of the subjects did not show an increase in psychomimetic symptoms after THC alone. Within responders, olanzapine reduced the effects of THC on the positive subscale (p=0.005). Other outcome measures included pharmacokinetics, eye movements, postural stability, pupil/iris ratio, and serum concentrations of cortisol and prolactin.	22.596.206		Centre for Human Drug Research	Centre for Human Drug Research				published	1	1	Published report
http://repo.napdi.org/NPDI-agZaLg	117	Goldenseal	Human Cytochrome P450 Inhibition and Metabolic-Intermediate Complex Formation By Goldenseal Extract and Its Methylenedioxyphenyl Components	PMID: 14570772	The concurrent use of herbal medicinals with prescription and over-the-counter drugs carries a risk for unanticipated adverse drug-botanical pharmacokinetic interactions, particularly as a result of cytochrome P450 (P450) inhibition. Extracts of goldenseal (Hydrastis canadensis) containing approximately equal concentrations ( approximately 17 mM) of two methylenedioxyphenyl alkaloids, berberine and hydrastine, inhibited with increasing potency (CYP2C9) diclofenac 4'-hydroxylation, (CYP2D6) bufuralol 1'-hydroxylation, and (CYP3A4) testosterone 6beta-hydroxylation activities in human hepatic microsomes. The inhibition of testosterone 6beta-hydroxylation activity was noncompetitive with an apparent Ki of 0.11% extract. Of the methylenedioxyphenyl alkaloids, berberine (IC50 = 45 microM) was the more inhibitory toward bufuralol 1'-hydroxylation and hydrastine (IC50 approximately 350 microM for both isomers), toward diclofenac 4'-hydroxylation. For testosterone 6beta-hydroxylation, berberine was the least inhibitory component (IC50 approximately 400 microM). Hydrastine inhibited testosterone 6beta-hydroxylation with IC50 values for the (+)- and (-)-isomers of 25 and 30 microM, respectively. For (-)-hydrastine, an apparent Ki value of 18 microM without preincubation and an NADPH-dependent mechanism-based inhibition with a kinactivation of 0.23 min(-1) and a KI of approximately 110 microM were determined. Cytochrome P450 metabolic-intermediate (MI) complex formation could be demonstrated for both hydrastine isomers. With expressed P450 isoforms, hydrastine formed a P450 MI complex with CYP2C9, CYP2D6, and CYP3A4. Coexpression of cytochrome b5 with the P450 isoforms enhanced the rate but not the extent of P450 MI complex formation.	14.570.772		College of Pharmacy, University of Utah	Department of Pharmacology and Toxicology				published	1	1	Published report
http://repo.napdi.org/NPDI-k8HdOg	795	Cannabis	Hemp (low CBD) extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-hemp-lowCBD-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-O6q4mg	831	Gou Teng	Identification of PXR activators from Uncaria rhynchophylla (Gou Teng)		Gou Teng extracts were found to dose-dependently activate PXR and induce CYP3A4 expression. New activators from Gou Teng were also discovered and demonstrated the half maximal effective concentration < 10 µM for PXR activation. Isocorynoxeine, rhynchophylline, isorhynchophylline, and corynoxeine were identified as PXR activators from Gou Teng extracts.	36.797.057		U Pitt, Duquesne-1	Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh; Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University				published	1	1	Published report
http://repo.napdi.org/NPDI-TAWrdg	811	Ivy leaf	Ivy leaf mixed parts extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-AHR-ivy-leaf-1	Natural Center for Natural Products Research			PXR fold activation results not available	published	1	1	Published report
http://repo.napdi.org/NPDI-Lm3PvA	155	Licorice	Cytochrome P450 inhibition by licorice species Glycyrrhiza uralensis and fourteen licorice constituents		The potential of licorice dietary supplements to interact with drug metabolism was evaluated by testing extracts of botanically identified licorice species Glycyrrhiza uralensis and 14 isolated licorice compounds for inhibition of 9 cytochrome P450 enzymes using a UHPLC-MS/MS cocktail assay. G. uralensis strongly inhibited CYP2B6 and moderately inhibited CYP2C8, CYP2C9 and CYP2C19. The licorice compounds isoliquiritigenin, licoricidin, licochalcone A, 18β-glycyrrhetinic acid, and glycycoumarin inhibited one or more members of the CYP2C family of enzymes. Glycycoumarin and licochalcone A inhibited CYP1A2, but only glycycoumarin inhibited CYP2B6. Isoliquiritigenin, glabridin and licoricidin competitively inhibited CYP3A4. The licorice species commonly used in botanical dietary supplements have varying potential for drug-botanical interactions as inhibitors of cytochrome P450 isoforms. Each species of licorice displays a unique profile of constituents with potential for drug interactions.	28.774.812		UIC	UIC	22/03/2017 12:00 AM	30/07/2017 12:00 AM		published	1	1	Published report
http://repo.napdi.org/NPDI-5Mf9Qw	97	Goldenseal	The Effect of Oxidation on Berberine-Mediated CYP1 Inhibition: Oxidation Behavior and Metabolite-Mediated Inhibition	PMID: 25953522	The protoberberine alkaloid berberine carries methylenedioxy moiety and exerts a variety of pharmacological effects, such as anti- inflammation and lipid-lowering effects. Berberine causes potent CYP1B1 inhibition, whereas CYP1A2 shows resistance to the inhibition. To reveal the influence of oxidative metabolism on CYP1 inhibition by berberine, berberine oxidation and the metabolite-mediated inhibition were determined. After NADPH-fortified preincubation of berberine with P450, the inhibition of CYP1A1 and CYP1B1 variants (CYP1B1.1, CYP1B1.3, and CYP1B1.4) by berberine was not enhanced, and CYP1A2 remained resistant. Demethyleneberberine was identified as the most abundant metabolite of CYP1A1- and CYP1B1-catalyzed oxidations, and thalifendine was generated at a relatively low rate. CYP1A1-catalyzed berberine oxidation had the highest maximal velocity (Vmax) and exhibited positive cooperativity, suggesting the assistance of substrate binding when the first substrate was present. In contrast, the demethylenation by CYP1B1 showed the property of substrate inhibition. CYP1B1-catalyzed berberine oxidation had low Km values, but it had Vmax values less than 8% of those of CYP1A1. The dissociation constants generated from the binding spectrum and fluorescence quenching suggested that the low Km values of CYP1B1-catalyzed oxidation might include more than the rate constants describing berberine binding. The natural protoberberine/berberine fmetabolites with methylenedioxy ring-opening (palmatine, jatrorrhizine, and demethyleneberberine) and the demethylation (thalifendine and berberrubine) caused weak CYP1 inhibition. These results demonstrated that berberine was not efficiently oxidized by CYP1B1, and metabolism-dependent irreversible inactivation was minimal. Metabolites of berberine caused a relatively weak inhibition of CYP1.	25.953.522		National Research Institute of Chinese Medicine	Divisions of Basic Chinese Medicine				published	1	1	Published report
http://repo.napdi.org/NPDI-d4aGfw	187	Cannabis	In Vitro Inhibition of Carboxylesterase 1 by Major Cannabinoids and Selected Metabolites		The escalating use of medical cannabis and significant recreational use of cannabis in recent years has led to a higher potential for metabolic interactions between cannabis or one or more of its components and concurrently used medications. Although there have been a significant number of in vitro and in vivo assessments of the effects of cannabis on cytochrome P450 and UDP-glucuronosyltransferase enzyme systems, there is limited information regarding the effects of cannabis on the major hepatic esterase, carboxylesterase 1 (CES1). In this study, we investigated the in vitro inhibitory effects of the individual major cannabinoids and metabolites Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), 11-nor-THC-carboxylic acid, and 11-hydroxy-THC on CES1 activity. S9 fractions from human embryonic kidney 293 cells stably expressing CES1 were used in the assessment of cannabinoid inhibitory effects. THC, CBD, and CBN each exhibited substantial inhibitory potency, and were further studied to determine their mechanism of inhibition and kinetic parameters. The inhibition of CES1 by THC, CBD, and CBN was reversible and appears to proceed through a mixed competitivenoncompetitive mechanism. The inhibition constant (Ki) values for THC, CBD, and CBN inhibition were 0.541, 0.974, and 0.263 mM (0.170, 0.306, and 0.0817 mg/ml), respectively. Inhibition potency was increased when THC, CBD, and CBN were combined. Compared with the potential unbound plasma concentrations attainable clinically, the Ki values suggest a potential for clinically significant inhibition of CES1 by THC and CBD. CBN, however, is expected to have a limited impact on CES1. Carefully designed clinical studies are warranted to establish the clinical significance of these in vitro findings.	30.833.288		UF	University of Florida				published	1	1	Published report
http://repo.napdi.org/NPDI-UmIRAQ	156	Licorice	Cytochrome P450 inhibition by licorice species Glycyrrhiza inflata and fourteen licorice constituents		The potential of licorice dietary supplements to interact with drug metabolism was evaluated by testing extracts of botanically identified licorice species Glycyrrhiza inflata and 14 isolated licorice compounds for inhibition of 9 cytochrome P450 enzymes using a UHPLC-MS/MS cocktail assay. G. inflata strongly inhibited CYP2C enzymes and moderately inhibited CYP1A2, CYP2B6, CYP2D6, and CYP3A4 (midazolam). The licorice compounds isoliquiritigenin, licoricidin, licochalcone A, 18β-glycyrrhetinic acid, and glycycoumarin inhibited one or more members of the CYP2C family of enzymes. Glycycoumarin and licochalcone A inhibited CYP1A2, but only glycycoumarin inhibited CYP2B6. Isoliquiritigenin, glabridin and licoricidin competitively inhibited CYP3A4, while licochalcone A was a mechanism-based inhibitor. The licorice species commonly used in botanical dietary supplements have varying potential for drug-botanical interactions as inhibitors of cytochrome P450 isoforms. Each species of licorice displays a unique profile of constituents with potential for drug interactions.	28.774.812		UIC	UIC	22/03/2017 12:00 AM	30/07/2017 12:00 AM		published	1	1	Published report
http://repo.napdi.org/NPDI-iLBKJw	835	Goldenseal	R21 Goldenseal Project		Inhibition of PMAT, THTR2, and OCT3 transporters were tested using both goldenseal extract and berberine. Two pharmacokinetic studies measured the Cmax, AUC, AUCR, half-life, and Tmax of metformin alone and in combination with other test articles (goldenseal extract, berberine, (-)-β-hydrastine, and imatinib).			WSU-1	WSU				published	3	3	Unpublished data submitted through a NaPDI form
http://repo.napdi.org/NPDI-j8alQQ	826	Ginger	Ginger root extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-ginger-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-SPpDlg	76	Goldenseal	Enzyme-inducing effects of berberine on cytochrome P450 1A2 in vitro and in vivo	PMID: 28893642	Aims: Berberine (BER) is an important anti-bacterial drug from Chinese herbal medicine and a novel drug candidate for preclinical development in recent years. Here we provide evidence that the effects of berberine on cytochrome P450 (CYP) 1A2 in vitro and in vivo. Main methods: Real-time polymerase chain reaction and western blotting analysis were employed to evaluate the CYP1A2 mRNA levels and protein expression. The enzyme activity was assessed by the metabolic rate of phenacetin to acetaminophen by LC-MS/MS method. Key findings: The results indicated that the CYP1A2 mRNA expression and enzyme activity in HepG2 cells after treated with BER (4.5 μg/ml) exhibited a significant induction (16.11-fold and 5.0-fold, respectively), which was consistent with those on rat liver microsomes (4.5-fold and 1.98-fold, respectively) by BER induction (10 mg/kg/ day, i.p.) ex vivo. Beside, BER induced CYP1A2 activity with increases in AUC0 − t and Cmax of acetaminophen and the Ke and t1/2 of phenacetin after oral administration of phenacetin (p < 0.05) in vivo. Significance: This study firstly reported the induction effect of BER on rats CYP1A2 by intraperitoneal route. But, BER didn't show significant induction effect on CYP1A2 by high-dose orally administrating to rats for 6 consecutive days due to the extremely low bioavailability. The potential drug-drug interactions were supposed to happen when the liver exposed to high dose of BER in vivo by changing administration route.	28.893.642		Changzheng Hospital	Department of Pharmacy				published	1	1	Published report
http://repo.napdi.org/NPDI-4zmpGg	81	Goldenseal	Time-Dependent Inhibition of CYP2C19 by Isoquinoline Alkaloids: In Vitro and In Silico Analysis	PMID: 26400396	The cytochrome P450 2C19 (CYP2C19) enzyme plays an important role in the metabolism of many commonly used drugs. Relatively little is known about CYP2C19 inhibitors, including compounds of natural origin, which could inhibit CYP2C19, potentially causing clinically relevant metabolism-based drug interactions. We evaluated a series (N = 49) of structurally related plant isoquinoline alkaloids for their abilities to interact with CYP2C19 enzyme using in vitro and in silico methods. We examined several common active alkaloids found in herbal products such as apomorphine, berberine, noscapine, and papaverine, as well as the previously identified mechanism-based inactivators bulbocapnine, canadine, and protopine. The IC50 values of the alkaloids ranged from 0.11 to 210 mM, and 42 of the alkaloids were confirmed to be time-dependent inhibitors of CYP2C19. Molec- ular docking and three-dimensional quantitative structure-activity relationship analysis revealed key interactions of the potent inhibitors with the enzyme active site. We constructed a comparative molecular field analysis model that was able to predict the inhibitory potency of a series of independent test molecules. This study revealed that many of these isoquinoline alkaloids do have the potential to cause clinically relevant drug interactions. These results highlight the need for studying more profoundly the potential interactions between drugs and herbal products. When further refined, in silico methods can be useful in the high-throughput prediction of P450 inhibitory potential of pharmaceutical compounds.	26.400.396		University of Eastern Finland	School of Pharmacy, Faculty of Health Sciences				published	1	1	Published report
http://repo.napdi.org/NPDI-Z6vbAA	79	Cannabis	Characterization of the structural determinants required for potent mechanism-based inhibition of human cytochrome P450 1A1 by cannabidiol	PMID: 24667653	We previously demonstrated that cannabidiol (CBD) was a potent mechanism-based inhibitor of human cytochrome P450 1A1 (CYP1A1). However, the moiety of CBD that contributes to the potent mechanism-based inhibition of human CYP1A1 remains unknown. Thus, the effects of compounds structurally related to CBD on CYP1A1 activity were examined with recombinant human CYP1A1 in order to characterize the structural requirements for potent inactivation by CBD. When preincubated in the presence of NADPH for 20min, olivetol, which corresponds to the pentylresorcinol moiety of CBD, enhanced the inhibition of the 7-ethoxyresorufin O-deethylase activity of CYP1A1. In contrast, d-limonene, which corresponds to the terpene moiety of CBD, failed to inhibit CYP1A1 activity in a metabolism-dependent manner. Pentylbenzene, which lacks two free phenolic hydroxyl groups, also did not enhance CYP1A1 inhibition. On the other hand, preincubation of the CBD-2'-monomethyl ether (CBDM) and CBD-2',6'-dimethyl ether (CBDD) enhanced the inhibition of CYP1A1 activity. Inhibition by cannabidivarin (CBDV), which possessed a propyl side chain, was strongly potentiated by its preincubation. Orcinol, which has a methyl group, augmented CYP1A1 inhibition, whereas its derivative without an alkyl side chain, resorcinol, did not exhibit any metabolism-dependent inhibition. The preincubation of CBD-hydroxyquinone did not markedly enhance CYP1A1 inhibition. We further confirmed that olivetol, CBDM, CBDD, CBDV, and orcinol, as well as CBD (kinact=0.215min(-1)), inactivated CYP1A1 activity; their kinact values were 0.154, 0.0638, 0.0643, 0.226, and 0.0353min(-1), respectively. These results suggest that the methylresorcinol structure in CBD may have structurally important roles in the inactivation of CYP1A1.	24.667.653		Hokuriku University	Hokuriku University				published	1	1	Published report
http://repo.napdi.org/NPDI-zlH6uA	90	Cannabis	Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes	PMID: 21704641	AIMS: Cannabidiol (CBD), one of the major constituents in marijuana, has been shown to be extensively metabolized by experimental animals and humans. However, human hepatic enzymes responsible for the CBD metabolism remain to be elucidated. In this study, we examined in vitro metabolism of CBD with human liver microsomes (HLMs) to clarify cytochrome P450 (CYP) isoforms involved in the CBD oxidations. MAIN METHODS: Oxidations of CBD in HLMs and recombinant human CYP enzymes were analyzed by gas chromatography/mass spectrometry. KEY FINDINGS: CBD was metabolized by pooled HLMs to eight monohydroxylated metabolites (6α-OH-, 6β-OH-, 7-OH-, 1″-OH-, 2″-OH-, 3″-OH-, 4″-OH-, and 5″-OH-CBDs). Among these metabolites, 6α-OH-, 6β-OH-, 7-OH-, and 4″-OH-CBDs were the major ones as estimated from the relative abundance of m/z 478, which was a predominant fragment ion of trimethylsilyl derivatives of the metabolites. Seven of 14 recombinant human CYP enzymes examined (CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) were capable of metabolizing CBD. The correlations between CYP isoform-specific activities and CBD oxidative activities in 16 individual HLMs indicated that 6β-OH- and 4″-OH-CBDs were mainly formed by CYP3A4, which was supported by inhibition studies using ketoconazole and an anti-CYP3A4 antibody. The correlation and inhibition studies also showed that CBD 6α-hydroxylation was mainly catalyzed by CYP3A4 and CYP2C19, whereas CBD 7-hydroxylation was predominantly catalyzed by CYP2C19. SIGNIFICANCE: This study indicated that CBD was extensively metabolized by HLMs. These results suggest that CYP3A4 and CYP2C19 may be major isoforms responsible for 6α-, 6β-, 7-, and/or 4″-hydroxylations of CBD in HLMs.	21.704.641		Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences	Hokuriku University				published	1	1	Published report
http://repo.napdi.org/NPDI-XM-YzA	134	Green tea	Green Tea Characterization of Material	UNCG-001	CoA for Green Tea.			UNCG	University of North Carolina - Greensboro			Data entered by EC via a Certificate of Analysis provided by UNCG.	published	3	3	Unpublished data submitted through a NaPDI form
http://repo.napdi.org/NPDI-5XFThQ	59	Goldenseal	Repeated administration of berberine inhibits cytochromes P450 in humans	PMID: 21870106	Authors proposed mechanism: Inhibitory effect of berberine on CYP2D6 activity may be caused by substrate competition. CYP2C9 did not metabolize berberine, further study about berberine and CYP2C9 gene regulation may provide evidence to clarify this alteration. CYP3A4 inhibition might be caused by berberine slowing the motility of the digestive system or suppressed mRNA expression Abstract: Purpose Berberine is a plant alkaloid that is widely used to treat gastrointestinal infections, diabetes, hypertension, and hypercholesterolemia. Many studies have reported interac- tions between berberine-containing products and cyto- chromes P450 (CYPs), but little is known about whether berberine alters CYP activities in humans, especially after repeated doses. Methods A two-phase randomized-crossover clinical study in healthy male subjects was performed. After 2 weeks of berberine (300 mg, t.i.d., p.o.) administration, midazolam, omeprazole, dextromethorphan, losartan, and caffeine were used to evaluate enzyme activities of CYP3A4, 2C19, 2D6, 2C9, and CYP1A2, respectively. Results A decrease in CYP2D6 activity was observed as the 0–8 h urinary dextromethorphan/dextrorphan increased ninefold (P < 0.01). In addition, losartan/E-3174 ratio doubled (P < 0.01) after BBR administration, indicating a decrease in CYP2C9 activity. CYP3A4 activity was also inhibited, as the Cmax, AUC0–∞, and AUC0–12 of midazolam were increased 38% (P < 0.05), 40% (P < 0.01), and 37% (P < 0.05) after with the placebo period, the Tmax and T1/2 of midazolam during BBR administration were prolonged from 3.03 ± 0.27 to 3.66 ± 0.37 h and 0.66 ± 0.08 to 0.99 ± 0.09 h, respectively; the oral clearance of midazolam was decreased 27% (P< 0.05); and the phenotypic indices of 1 h midazolam/1′- hydroxymidazolam increased 59% (P < 0.01). There were no statistically significant differences in the pharmacokinetic parameters of the other probe drugs between placebo and the BBR-treated group. Conclusions Repeated administration of berberine (300 mg, t.i.d., p.o.) decreased CYP2D6, 2C9, and CYP3A4 activities. Drug-drug interactions should be considered when berberine is administered.	21.870.106		XiangYa School of Medicine	Institute of Clinical Pharmacology				published	1	1	Published report
http://repo.napdi.org/NPDI-g-PM9w	794	Coptis	Coptis rhizome extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-coptis-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-C-vzvw	84	Goldenseal	Poor permeability and absorption affect the activity of four alkaloids from Coptis	PMID: 26352530	Coptidis rhizoma (Coptis) and its alkaloids exert various pharmacological functions in cells and tissues; however, the oral absorption of these alkaloids requires further elucidation. The present study aimed to examine the mechanism underlying the poor absorption of alkaloids, including berberine (BER), coptisine (COP), palmatine (PAL) and jatrorrhizine (JAT). An ultra-performance liquid chromatography (UPLC) method was validated for the determination of BER, COP, PAL and JAT in the above experimental medium. In addition, the apparent oil‐water partition coefficient (Po/w); apparent permeability coefficient (Papp), determined using a parallel artificial membrane permeability assay (PAMPA)plate; membrane retention coefficient (R %); and effect of P-glycoprotein (P-gp) inhibitor on the Papp of the four alkaloids were investigated. The intestinal absorption rate constant (Ka) and absorption percentage (A %) of the four alkaloids were also determined. The results of the present study demonstrated that the Po/w of the four alkaloids in 0.1 mol·l-1 HCl medium was significantly higher (P<0.01), compared with those of the alkaloids in phosphate buffer (pH 7.4). The Papp of BER was 1.0-1.2x10-6 cm·s-1, determined using a PAMPA plate, and the Papp of BER, COP, PAL and JAT decreased sequentially. The concentrations of the four alkaloids on the apical-to-basolateral (AP-BL) surface and the basolateral-to-apical (BL-AP) surface increased in a linear manner, with increasing concentrations between 10 and 100 μmol. In addition, the transportation ofBER on the BL‐AP surface was significantly faster (P<0.01), compared with that on the AP-BL surface and, following the addition of verpamil (a P-gp inhibitor), the Papp (AP-BL) of the four alkaloids increased, whereas the Papp (BL-AP) wassignificantly decreased (P<0.01). The rat intestinal perfusion experiment demonstrated that the four alkaloids were poorly absorbed; however, the Ka of BER was significantly higher, compared with the three other alkaloids. Furthermore, the A % and Ka provided evidence that the absorption of BER was increased in the jejunum, compared with in the ileum. In conclusion, the four alkaloids from Coptis appeared to be poorly absorbed, determined using a shake flask, pre‐coated PAMPA plates, a Caco-2 cell monolayer model and intestinal perfusion; however, absorption was higher in the jejunum than in the ileum. Among the four alkaloids, the permeability of BER was markedly higher than the others, and P‐gp efflux had a significant effect on the absorption of those alkaloids.	26.352.530		Guang'anmen Hospital, China Academy of Chinese Medical Sciences	Department of Endocrinology				published	1	1	Published report
http://repo.napdi.org/NPDI-qOTUkQ	74	Cannabis	The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir	PMID: 11872997	Background and objectives: The use of cannabinoids for appetite stimulation and the management of wasting and antiretroviral side-effects has become a common practice in the care of HIV-infected individuals. We present pharmacokinetic data from a randomized placebo-controlled study designed to evaluate the metabolic effects of smoked marijuana and dronabinol in HIV-infected patients receiving indinavir (IDV) or nelfinavir (NFV). Methods: Subjects on stable regimens containing IDV 800 mg every 8 h (n = 28) or NFV 750 mg three time a day (n = 34) were randomized to one of three treatment arms: 3.95% THC marijuana cigarettes, dronabinol 2.5 mg capsules or placebo capsules administered three times daily. Serial blood sampling was performed at baseline and on day 14 of treatment. The changes in NFV and IDV pharmacokinetics were measured as the median percentage change from baseline. Results: At day 14, the 8-h area under the curve (AUC8) changed by 􏰟10.2% (P 􏰦 0.15), maximum concentration (Cmax) by 􏰟17.4% (P 􏰦 0.46), and minimum concentration (Cmin) by 􏰟12.2% (P 􏰦 0.28) for patients in the NFV marijuana arm (n 􏰦 11). Similar decreases had occurred by day 14 among patients in the IDV marijuana arm (n 􏰦 9): AUC8 had changed by 􏰟14.5% (P 􏰦 0.074), Cmax by 􏰟14.1% (P 􏰦 0.039), and Cmin by 􏰟33.7% (P 􏰦 0.65). Conclusion: Despite a statistically significant decrease in Cmax of IDV in the marijuana arm, the magnitude of changes in IDV and NFV pharmacokinetic parameters in the marijuana arm are likely to have no short-term clinical consequence. The use of marijuana or dronabinol is unlikely to impact antiretroviral efficacy.	11.872.997		University of California, San Francisco	University of California, San Francisco				published	1	1	Published report
http://repo.napdi.org/NPDI-9V_SXw	141	Cannabis	Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19.		The present study investigated the inhibitory effect of cannabidiol (CBD), a major constituent of marijuana, on the catalytic activity of cytochrome P450 2C19 (CYP2C19). (S)-Mephenytoin 4'-hydroxylase activities of human liver microsomes (HLMs) and recombinant CYP2C19 were inhibited by CBD in a concentration-dependent manner (IC₅₀ = 8.70 and 2.51 µM, respectively). Omeprazole 5-hydroxylase and 3-O-methylfluorescein O-demethylase activities in recombinant CYP2C19 were also strongly inhibited by CBD (IC₅₀ = 1.55 and 1.79 µM, respectively). Kinetic analysis for inhibition revealed that CBD showed a mixed-type inhibition against (S)-mephenytoin 4'-hydroxylation by recombinant CYP2C19. To clarify the structural requirements for CBD-mediated CYP2C19 inhibition, the effects of CBD-related compounds on CYP2C19 activity were examined. Olivetol inhibited the (S)-mephenytoin 4'-hydroxylase activity of recombinant CYP2C19 with the IC₅₀ value of 15.3 µM, whereas d-limonene slightly inhibited the activity (IC₅₀ > 50 µM). The inhibitory effect of CBD-2'-monomethyl ether (IC₅₀ = 1.88 µM) on CYP2C19 was comparable to that of CBD, although the inhibitory potency of CBD-2',6'-dimethyl ether (IC₅₀ = 14.8 µM) was lower than that of CBD. Cannabidivarin, possessing a propyl side chain, showed slightly less potent inhibition (IC₅₀ = 3.45 µM) as compared with CBD, whereas orcinol and resorcinol did not inhibit CYP2C19 activity at all. These results indicate that CBD caused potent CYP2C19 inhibition, in which one free phenolic hydroxyl group and the pentyl side chain of CBD may play important roles.	23.318.708		Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.	Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.			A published report from the literature. Data entered by CB and review by RB.	published	1	1	Published report
http://repo.napdi.org/NPDI-dIgOyA	171	Kratom	Metabolite profiling and identification of enzymes responsible for the metabolism of mitragynine, the major alkaloid of Mitragyna speciosa (kratom)		Mitragynine is the major indole-based alkaloid of Mitragyna speciosa (kratom). Decoctions (teas) of the plant leaves have been used traditionally for cough, diarrhoea, pain, hypertension and for the treatment of opioid addiction. In the West, kratom has become increasingly utilized for mood elevation, pain treatment and as a means of self-treating opioid addiction. Metabolic pathways of mitragynine were identified in human liver microsomes (HLM) and S9 fractions. A total of thirteen metabolites were identified, four oxidative metabolites and a metabolite formed by demethylation at the 9-methoxy group were the major metabolites of mitragynine. The cytochrome P450 enzymes involved in the metabolism of mitragynine were identified using selective chemical inhibitors of HLM and recombinant cytochrome P450. The metabolism of mitragynine was predominantly carried out through the CYP3A4 with minor contributions by CYP2D6 and CYP2C9. The formation of five oxidative metabolites (Met2, Met4, Met6, Met8 and Met11) was catalyzed by the CYP3A4. In summary, mitragynine was extensively metabolized in HLM primarily to O-demethylated and monooxidative metabolites. The CYP3A4 enzyme plays a predominant role in the metabolic clearance of mitragynine and also in the formation of 7-hydroxymitragynine (Met2), a known active minor alkaloid identified in the leaf material.	30.547.698	625853292	UF	University of Florida				published	1	1	Published report
http://repo.napdi.org/NPDI-Rvn9SQ	190	Cannabis	Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes		In this study, tetrahydrocannabinols (THCs) were mainly oxidized at the 11-position and allylic sites at the 7α-position for Δ⁸-THC and the 8β-position for Δ⁹-THC by human hepatic microsomes. Cannabinol (CBN) was also mainly metabolized to 11-hydroxy-CBN and 8-hydroxy-CBN by the microsomes. The 11-hydroxylation of three cannabinoids by the microsomes was markedly inhibited by sulfaphenazole, a selective inhibitor of CYP2C enzymes, while the hydroxylations at the 7α-(Δ⁸-THC), 8β-(Δ⁹-THC) and 8-positions (CBN) of the corresponding cannabinoids were highly inhibited by ketoconazole, a selective inhibitor of CYP3A enzymes. Human CYP2C9-Arg expressed in the microsomes of human B lymphoblastoid cells efficiently catalyzed the 11-hydroxylation of Δ⁸-THC (7.60 nmol/min/nmol CYP), Δ⁹-THC (19.2 nmol/min/nmol CYP) and CBN (6.62 nmol/min/nmol CYP). Human CYP3A4 expressed in the cells catalyzed the 7α-(5.34 nmol/min/nmol CYP) and 7β-hydroxylation (1.39 nmol/min/nmol CYP) of Δ⁸-THC, the 8β-hydroxylation (6.10 nmol/min/nmol CYP) and 9α,10α-epoxidation (1.71 nmol/min/nmol CYP) of Δ⁹-THC, and the 8-hydroxylation of CBN (1.45 nmol/min/nmol CYP). These results indicate that CYP2C9 and CYP3A4 are major enzymes involved in the 11-hydroxylation and the 8-(or the 7-) hydroxylation, respectively, of the cannabinoids by human hepatic microsomes. In addition, CYP3A4 is a major enzyme responsible for the 7α- and 7β-hydroxylation of Δ⁸-THC, and the 9α,10α-epoxidation of Δ⁹-THC.	17.303.175		HU	Hokuriku University				published	1	1	Published report
http://repo.napdi.org/NPDI-UC_DUA	16	Green tea	Blood and Urine Levels of Tea Catechins after Ingestion of Different Amounts of Green Tea by Human Volunteers	PMID: 9568793	The inhibitory activity of tea against tumorigenesis has been demonstrated in many animal models and has been suggested by some epidemiological studies. Such activity has generally been attributed to tea catechins. To understand the bioavailability of tea catechins in humans, we gave 18 individuals different amounts of green tea and measured the time-dependent plasma concentrations and urinary excretion of tea catechins. After taking 1.5, 3.0, and 4.5 g of decaffeinated green tea solids (dissolved in 500 ml of water), the maximum plasma concentration (Cmax) of (-)-epigallocatechin-3-gallate (EGCG) was 326 ng/ml, the Cmax of (-)-epigallocatechin (EGC) was 550 ng/ml, and the Cmax of (-)-epicatechin (EC) was 190 ng/ml. These Cmax values were observed at 1.4-2.4 h after ingestion of the tea preparation. When the dosage was increased from 1.5 to 3.0 g, the Cmax values increased 2.7-3.4-fold, but increasing the dose to 4.5 g did not increase the Cmax values significantly, which suggested a saturation phenomenon. The half-life of EGCG (5.0-5.5 h) seemed to be higher than the half-life of EGC or EC (2.5-3.4 h). EGC and EC, but not EGCG, were excreted in the urine. Over 90% of the total urinary EGC and EC was excreted within 8 h. When the tea dosage was increased, the amount of EGC and EC excretion seemed to increase, but a clear dose-response relationship was not observed. The present study provides basic pharmacokinetic parameters of green tea catechins in humans; these parameters may be used to estimate the levels of these compounds after drinking tea.	9.568.793		Rugters University	Laboratory for Cancer Research, Rugters University			This is a study reported in the literature. The data was entered by JY and reviewed by JS.	published	1	1	Published report
http://repo.napdi.org/NPDI-luckpg	103	Goldenseal	An ex vivo approach to botanical-drug interactions: A proof of concept study	PMID: 25623616	Ethnopharmacological relevance—Botanical medicines are frequently used in combination with therapeutic drugs, imposing a risk for harmful botanical-drug interactions (BDIs). Among the existing BDI evaluation methods, clinical studies are the most desirable, but due to their expense and protracted time-line for completion, conventional in vitro methodologies remain the most frequently used BDI assessment tools. However, many predictions generated from in vitro studies are inconsistent with clinical findings. Accordingly, the present study aimed to develop a novel ex vivo approach for BDI assessment and expand the safety evaluation methodoloy in applied ethnopharmacological research. Materials and Methods—This approach differs from conventional in vitro methods in that rather than botanical extracts or individual phytochemicals being prepared in artificial buffers, human plasma/serum collected from a limited number of subjects administered botanical supplements was utilized to assess BDIs. To validate the methodology, human plasma/serum samples collected from healthy subjects administered either milk thistle or goldenseal extracts were utilized in incubation studies to determine their potential inhibitory effects on CYP2C9 and CYP3A4/5, respectively. Silybin A and B, two principal milk thistle phytochemicals, and hydrastine and berberine, the purported active constituents in goldenseal, were evaluated in both phosphate buffer and human plasma based in vitro incubation systems. Results—Ex vivo study results were consistent with formal clinical study findings for the effect of milk thistle on the disposition of tolbutamide, a CYP2C9 substrate, and for goldenseal’s influence on the pharmacokinetics of midazolam, a widely accepted CYP3A4/5 substrate. Compared to conventional in vitro BDI methodologies of assessment, the introduction of human plasma into the in vitro study model changed the observed inhibitory effect of silybinA, silybin B and hydrastine and berberine on CYP2C9 and CYP3A4/5, respectively, results which more closely mirrored those generated in clinical study. Conclusions—Data from conventional buffer-based in vitro studies were less predictive than the ex vivo assessments. Thus, this novel ex vivo approach may be more effective at predicting clinically relevant BDIs than conventional in vitro methods.	25.623.616		University of Michigan College of Pharmacy Ann Arbor	Department of Clinical, Social and Administrative Sciences				published	1	1	Published report
http://repo.napdi.org/NPDI-m-U3YQ	115	Cannabis	The multidrug transporter ABCG2 (BCRP) is inhibited by plant-derived cannabinoids.	PMID: 17906686	BACKGROUND AND PURPOSE: Cannabinoids are used therapeutically for the palliation of the adverse side effects associated with cancer chemotherapy. However, cannabinoids also inhibit both the activity and expression of the multidrug transporter, P-glycoprotein in vitro. Here we address the interaction of cannabinol (CBN), cannabidiol (CBD) and delta 9-tetrahydrocannabinol (THC) with the related multidrug transporter, ABCG2. EXPERIMENTAL APPROACH: Cannabinoid inhibition of Abcg2/ABCG2 was assessed using flow cytometric analysis of substrate accumulation and ATPase activity assays. The cytotoxicity and chemosensitization by cannabinoids was determined with cell viability assays. Expression of cannabinoid and vanilloid receptors was assessed using reverse transcriptase polymerase chain reaction, and cannabinoid modulation of ABCG2 expression was examined using immunoblotting. KEY RESULTS: CBN, CBD and THC increased the intracellular accumulation of the Abcg2/ABCG2 substrate, mitoxantrone, in an over-expressing cell line. The THC metabolite, (-)-11-nor-9-carboxy-delta 9-THC was much less potent. The plant cannabinoids inhibited both basal and substrate stimulated ATPase activity of human ABCG2. Cannabinoid cytotoxicity occurred in the absence of known cannabinoid cell surface receptors, and only at concentrations higher than those required for Abcg2/ABCG2 inhibition. Sub-toxic concentrations of the cannabinoids resensitized the overexpressing cell line to the cytotoxic effect of Abcg2/ABCG2 substrates, mitoxantrone and topotecan. This occurred in the absence of any effect on ABCG2 expression. CONCLUSIONS AND IMPLICATIONS: Cannabinoids are novel Abcg2/ABCG2 inhibitors, reversing the Abcg2-mediated multidrug-resistant phenotype in vitro. This finding may have implications for the co-administration of cannabinoids with pharmaceuticals that are ABCG2 substrates.	17.906.686		The Discipline of Pharmacology	The University of Sydney				published	1	1	Published report
http://repo.napdi.org/NPDI-vQCHYg	148	Kratom	Characterization of Kratom material	cb_14				UNCG	UNCG				published	3	3	Unpublished data submitted through a NaPDI form
http://repo.napdi.org/NPDI-5Vo0XQ	810	Licorice	Licorice root extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-licorice-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-RTaSkA	4	Green tea	Inhibitory effects of various beverages on ritodrine sulfation by recombinant human sulfotransferase isoforms SULT1A1 and SULT1A3	PMID:16078151		16.078.151		T2	Multiple academic institutions in Japan			This is a study reported in the literature. The data was entered by RB and reviewed by JY.	published	1	1	Published report
http://repo.napdi.org/NPDI-Yknaag	53	Kratom	P-glycoprotein interactions of novel psychoactive substances – Stimulation of ATP consumption and transport across Caco-2 monolayers		In contrast to drugs for therapeutic use, there are only few data available concerning interactions between P-glycoprotein (P-gp) and drugs of abuse (DOA). In this work, interactions between structurally diverse DOA and P-gp were investigated using different strategies. First, the effect on the P-gp ATPase activity was studied by monitoring of ATP consumption after addition to recombinant, human P-gp. Second, DOA showing an increased ATP consumption were further characterized regarding their transport across filter grown Caco-2- monolayers. Analyses were performed by luminescence and liquid chromatography–mass spectrometry, respectively. Among the nine DOA initially screened, benzedrone, diclofensine, glaucine, JWH-200, MDBC, WIN-55,212-2 showed an increase of ATP consumption in the ATPase stimulation assay. In Caco-2 transport studies, Glaucine, JWH-200, mitragynine, WIN-55,212-2 could moreover be identified as non-transported substrates, but inhibitors of P-gp activity. Thus, drug– drug or drug–food interactions should be very likely for these compounds	25.637.762	602076267	Saarland University	Department of Experimental and Clinical Toxicology				published	1	1	Published report
http://repo.napdi.org/NPDI-hKjwcg	92	Goldenseal	Organic anion-transporting polypeptides contribute to the hepatic uptake of berberine	PMID: 26068524	The purpose of this study was to investigate the mechanism of hepatic uptake of berberine. Berberine accumulation in hepatocytes was found to be highly dependent on active uptake, which could not be explained by liver organic cation transporter (OCT) alone. Our studies indicated that berberine uptake was significantly suppressed by rifampicin, cyclosporine A and glycyrrhizic acid, which act as specific inhibitors of different Oatp isoforms (Oatp1a1, Oatp1a4 and Oatp1b2) in rat hepatocytes. The combination of OCT and OATP inhibitors further reduced berberine accumulation in both rat and human hepatocytes. The uptake of berberine could be increased in human HEK293-OATP1B3 but not in OATP1B1-transfected HEK 293 cells. Rifampicin could reduce the berberine liver extraction ratio (ER) and double its concentration in the effluent in isolated rat livers. Further in vivo study indicated that berberine plasma exposure could be significantly increased by co-administration of the OATP inhibitor rifampicin or the substrate rosuvastatin. In conclusion, this study demonstrated that both OCT and OATP contribute to the accumulation of berberine in the liver. OATPs may have important roles in berberine liver disposition and potential clinically relevant drug–drug interactions.	26.068.524		Jiangsu University	Institute of Life Sciences				published	1	1	Published report
http://repo.napdi.org/NPDI--2FOpA	23	Green tea	Pharmacokinetics and Safety of Green Tea Polyphenols after Multiple-Dose Administration of Epigallocatechin Gallate and Polyphenon E in Healthy Individuals	PMID:12960117	PURPOSE: Green tea and green tea polyphenols have been shown to possess cancer preventive activities in preclinical model systems. In preparation for future green tea intervention trials, we have conducted a clinical study to determine the safety and pharmacokinetics of green tea polyphenols after 4 weeks of daily p.o. administration of epigallocatechin gallate (EGCG) or Polyphenon E (a defined, decaffeinated green tea polyphenol mixture). In an exploratory fashion, we have also determined the effect of chronic green tea polyphenol administration on UV-induced erythema response. EXPERIMENTAL DESIGN: Healthy participants with Fitzpatric skin type II or III underwent a 2-week run-in period and were randomly assigned to receive one of the five treatments for 4 weeks: 800 mg EGCG once/day, 400 mg EGCG twice/day, 800 mg EGCG as Polyphenon E once/day, 400 mg EGCG as Polyphenon E twice/day, or a placebo once/day (8 subjects/group). Samples were collected and measurements performed before and after the 4-week treatment period for determination of safety, pharmacokinetics, and biological activity of green tea polyphenol treatment. RESULTS: Adverse events reported during the 4-week treatment period include excess gas, upset stomach, nausea, heartburn, stomach ache, abdominal pain, dizziness, headache, and muscle pain. All of the reported events were rated as mild events. For most events, the incidence reported in the polyphenol-treated groups was not more than that reported in the placebo group. No significant changes were observed in blood counts and blood chemistry profiles after repeated administration of green tea polyphenol products. There was a >60% increase in the area under the plasma EGCG concentration-time curve after 4 weeks of green tea polyphenol treatment at a dosing schedule of 800 mg once daily. No significant changes were observed in the pharmacokinetics of EGCG after repeated green tea polyphenol treatment at a regimen of 400 mg twice daily. The pharmacokinetics of the conjugated metabolites of epigallocatechin and epicatechin were not affected by repeated green tea polyphenol treatment. Four weeks of green tea polyphenol treatment at the selected dose and dosing schedule did not provide protection against UV-induced erythema. CONCLUSIONS: We conclude that it is safe for healthy individuals to take green tea polyphenol products in amounts equivalent to the EGCG content in 8-16 cups of green tea once a day or in divided doses twice a day for 4 weeks. There is a >60% increase in the systemic availability of free EGCG after chronic green tea polyphenol administration at a high daily bolus dose (800 mg EGCG or Polyphenon E once daily).	12.960.117		Arizona Cancer Center	Arizona Cancer Center, The University of Arizona			This is a study reported in the literature. The data was entered by JY and reviewed by JS (entries not complete).	published	1	1	Published report
http://repo.napdi.org/NPDI-SNlg1w	814	Goatweed	St. John's wort mixed parts extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-st.-johns-wort-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-XnaDAw	791	Coleus	Coleus stem extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-coleus-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-gTt8Dw	58	Cannabis	Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans	PMID: 25748562	Objectives — Cannabidiol (CBD) is hypothesized as a potential treatment for opioid addiction, with safety studies an important first step for medication development. We determined CBD safety and pharmacokinetics when administered concomitantly with a high-potency opioid in healthy subjects. Methods — This double-blind, placebo-controlled cross-over study of CBD co-administered with intravenous fentanyl, was conducted at the Clinical Research Center in Mount Sinai Hospital, a tertiary care medical center in New York City. Participants were healthy volunteers aged 21–65 years with prior opioid exposure, regardless of route. Blood samples were obtained before and after 400 or 800 mg CBD pretreatment, followed by a single 0.5 (Session 1) or 1.0mcg/Kg (Session 2) intravenous fentanyl dose. The primary outcome was the Systematic Assessment for Treatment Emergent Events (SAFTEE) to assess safety and adverse effects. CBD peak plasma concentrations, time to reach peak plasma concentrations (tmax), and area under the curve (AUC) were measured. Results — SAFTEE data were similar between groups without respiratory depression or cardiovascular complications during any test session. Following low dose CBD, tmax occurred at 3 and 1.5h (Sessions 1 and 2, respectively). Following high dose CBD, tmax occurred at 3 and 4h in Sessions 1 and 2, respectively. There were no significant differences in plasma CBD or cortisol (AUC p=NS) between sessions. Conclusions — CBD does not exacerbate adverse effects associated with intravenous fentanyl administration. Co-administration of CBD and opioids was safe and well tolerated. These data provide the foundation for future studies examining CBD as a potential treatment for opioid abuse.	25.748.562		The Icahn School of Medicine at Mount Sinai	The Icahn School of Medicine at Mount Sinai				published	1	1	Published report
http://repo.napdi.org/NPDI-dCfz1g	1	Green tea	Inhibition by green tea catechins of metabolic activation of procarcinogens by human cytochrome P450	PMID:11470492	Inhibition by green tea catechins of metabolic activation of procarcinogens by human cytochrome P450.	11.470.492		T1	Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University			This is a study reported in the literature. Data was entered by RB (did not enter information about metabolic activation of procarcinogens) and reviewed by JS (entries not complete - please add positive control data and negative data - No significant inhibition of CYP1A1, CYP1A2, CYP2A6, CYP2C9, CYP2E1, or CYP3A4 by (-)-epicatechin or (-)-epigallocatechin was observed at concentrations up to 100 µM in cell membrane fractions with the expression of the respective CYP enzyme together with P450 reductase [one negative entry, CYP1A1 non-inhibition by (-)-epicatechin, has been added by JS as an example]).	published	1	1	Published report
http://repo.napdi.org/NPDI-joEW1A	793	Boswellia	Boswellia resin extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-boswellia-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-EiXGKA	111	Goldenseal	An in vitro Evaluation of Cytochrome P450 Inhibition and P-Glycoprotein Interaction with Goldenseal, Ginkgo biloba, Grape Seed, Milk Thistle, and Ginseng Extracts and Their Constituents	PMID: 17611934	Drug-herb interactions can result from the modulation of the activities of cytochrome P450 (P450) and/or drug transporters. The effect of extracts and individual constituents of goldenseal, Ginkgo biloba (and its hydrolyzate), grape seed, milk thistle, and ginseng on the activities of cytochrome P450 enzymes CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 in human liver microsomes were determined using enzyme-selective probe substrates, and their effect on human P-glycoprotein (Pgp) was determined using a baculovirus expression system by measuring the verapamil-stimulated, vanadate-sensitive ATPase activity. Extracts were analyzed by HPLC to standardize their concentration(s) of constituents associated with the pharmacological activity, and to allow comparison of their effects on P450 and Pgp with literature values. Many of the extracts/constituents exerted > or = 50 % inhibition of P450 activity. These include those from goldenseal (normalized to alkaloid content) inhibiting CYP2C8, CYP2D6, and CYP3A4 at 20 microM, ginkgo inhibiting CYP2C8 at 10 microM, grape seed inhibiting CYP2C9 and CYP3A4 at 10 microM, milk thistle inhibiting CYP2C8 at 10 microM, and ginsenosides F1 and Rh1 (but not ginseng extract) inhibiting CYP3A4 at 10 microM. Goldenseal extracts/constituents (20 microM, particularly hydrastine) and ginsenoside Rh1 stimulated ATPase at about half of the activity of the model substrate, verapamil (20 microM). The data suggest that the clearance of a variety of drugs may be diminished by concomitant use of these herbs via inhibition of P450 enzymes, but less so by Pgp-mediated effects.	17.611.934		RTI International, Research Triangle Park, NC, USA	Health Sciences Unit, Science and Engineering				published	1	1	Published report
http://repo.napdi.org/NPDI-f1iDGA	780	Kratom	Clinical Pharmacokinetic Assessment of Kratom (Mitragyna speciosa), a Botanical Product with Opioid-like Effects, in Healthy Adult Participants		Increasing use of the botanical kratom to self-manage opioid withdrawal and pain has led to increased kratom-linked overdose deaths. Despite these serious safety concerns, rigorous fundamental pharmacokinetic knowledge of kratom in humans remains lacking. We assessed the pharmacokinetics of a single low dose (2 g) of a well-characterized kratom product administered orally to six healthy participants. Median concentration-time profiles for the kratom alkaloids examined were best described by a two-compartment model with central elimination. Pronounced pharmacokinetic differences between alkaloids with the 3S configuration (mitragynine, speciogynine, paynantheine) and alkaloids with the 3R configuration (mitraciliatine, speciociliatine, isopaynantheine) were attributed to differences in apparent intercompartmental distribution clearance, volumes of distribution, and clearance. Based on noncompartmental analysis of individual concentration-time profiles, the 3S alkaloids exhibited a shorter median time to maximum concentration (1-2 vs. 2.5-4.5 h), lower area under the plasma concentration-time curve (430-490 vs. 794-5120 nM × h), longer terminal half-life (24-45 vs. ~12-18 h), and higher apparent volume of distribution during the terminal phase (960-12,700 vs. ~46-130 L) compared to the 3R alkaloids. Follow-up mechanistic in vitro studies suggested differential hepatic/intestinal metabolism, plasma protein binding, blood-to-plasma partitioning, and/or distribution coefficients may explain the pharmacokinetic differences between the two alkaloid types. This first comprehensive pharmacokinetic characterization of kratom alkaloids in humans provides the foundation for further research to establish safety and effectiveness of this emerging botanical product.	35.335.999		WSU-1	Department of Pharmaceutical Sciences, Washington State University				published	1	1	Published report
http://repo.napdi.org/NPDI-UXOaUA	60	Cannabis	A phase I study to assess the effect of food on the single dose bioavailability of the THC/CBD oromucosal spray	PMID: 23052407	Purpose To assess the effect of food on the single-dose bioavailability of delta-9-tetrahydrocannabinol (THC)/can- nabidiol (CBD) spray, an endocannabinoid system modula- tor, when administered to healthy male subjects. Methods Twelve subjects took part in this fed–fasted cross- over study and received a single dose of THC/CBD spray (4 sprays 0 10.8 mg THC + 10 mg CBD) in the fasted then fed state (or vice versa) with a 3-day wash-out period between treatments. Plasma samples were collected at designated time- points for analysis of CBD, THC, and its active metabolite, 11-hydroxy delta-9-tetrahydrocannabinol (11-OH-THC). Results Statistically significant increases in the mean area under the curve (AUC) and mean maximum plasma drug concentration (Cmax) were observed in subjects during fed conditions. Mean AUC and Cmax were one to three-fold higher for THC and 11-OH-THC, and five and three-fold higher for CBD respectively during fed conditions. A large inter-subject variability in exposure from the same dose was observed, particularly for THC. The Cmax for THC in fed versus fasted subjects was higher in 7 subjects (4.80– 14.91 ng/ml) and lower in 5 subjects (2.81–3.51 ng/ml) compared with the mean Cmax of 3.98 ng/ml (range 0.97– 9.34 ng/ml) observed in the fasted state. Increases in mean AUC(0–t), AUC(0–inf), and Cmax for THC, CBD, and 11-OH-THC in the fed state were within the range of inter-subject variability, which was considerable. Food also appeared to delay the time to peak concentration (Tmax) of all analytes by approximately 2–2.5 h. Only mild adverse events were reported. Conclusions The THC/CBD spray was well tolerated in male subjects at a single dose of four sprays. The large inter-subject variability in exposure suggests that the changes observed are unlikely to be clinically relevant.	23.052.407		GW Pharma Ltd	GW Pharma Ltd				published	1	1	Published report
http://repo.napdi.org/NPDI-rRRoQw	105	Goldenseal	Inhibition of organic cation transporter 2 and 3 may be involved in the mechanism of the antidepressant-like action of berberine	PMID: 24246570	Organic cation transporter 2 (OCT2) and 3 (OCT3) are low-affinity, high-capacity transporters (uptake-2) expressed in the central nervous system (CNS) and other major organs. Proven to be essential components in the CNS functions, OCT2 and OCT3 are suggested as potential targets of antidepressant therapeutics recently. Berberine, an active constituent derived from many medicinal plants, such as Coptis chinensis, has been reported to possess antidepressant-like action in the tail suspension test and forced swim test with elevated serotonin/ norepinephrine/dopamine (5-HT/NE/DA) level in mouse brain; however the mechanism has not been elucidated. In consideration of the relation between OCT2/3 and antidepressant action, and the characteristic of berberine as an organic cation, we investigated the potential involvement of OCT2 and OCT3 in the antidepressant-like action of berberine in the present study. The results in mouse brain synaptosomes demonstrated that uptake-2 inhibition might play a notable role in enhanced serotonergic and noradrenergic effects induced by berberine. The inhibitory study in transfected MDCK cells displayed that berberine is a potent inhibitor of human OCT2 and OCT3, and its IC50values for inhibition of transporter-mediated 5-HT/NE uptake are between 0.1 and 1 μM. In addition, berberine was identified as a substrate of hOCT2 and hOCT3. In conclusion, berberine is a substrate and an inhibitor of hOCT2 and hOCT3, and its inhibition on OCT2- and OCT3-mediated 5-HT and NE uptake may contribute to the enhanced monoamine neurotransmission in mouse brain. It was deduced that the inhibition of OCT2 and OCT3 probably be implicated in the mechanism of antidepressant-like action.	24.246.570		College of Pharmaceutical Sciences, Zhejiang University	Department of Pharmaceutical Analysis and Drug Metabolism				published	1	1	Published report
http://repo.napdi.org/NPDI-fLne_g	75	Goldenseal	Influence of Goldenseal Root on the Pharmacokinetics of Indinavir	PMID: 14551183	Goldenseal root was identified as the most potent inhibitor of CYP3A4 in a study that tested 21 popular herbal products for in vitro inhibitory activity. The purpose of this investigation was to examine the influence of goldenseal root on the dispo- sition of the CYP3A4 substrate indinavir in humans. Using a crossover study design, the pharmacokinetics of indinavir were characterized in 10 healthy volunteers before and after 14 days of treatment with goldenseal root (1140 mg twice daily). Indinavir was given as a single 800-mg oral dose, and blood samples were collected for 8 hours following the dose. No statistically significant differences in peak concentration (11.6 vs. 11.9 mg/L) or oral clearance (26.8 vs. 23.9 mg•h/L) were observed following treatment with goldenseal root. Half-life and time to reach peak concentration were also un- changed by goldenseal. These results suggest that patients being treated with indinavir can safely take goldenseal root and that interactions with other drugs metabolized by CYP3A4 in the liver are unlikely.	14.551.183		Eugene Applebaum College of Pharmacy and Health Sciences	Department of Pharmacy Practice				published	1	1	Published report
http://repo.napdi.org/NPDI-9C7QHg	124	Kratom	Effects of mitragynine and 7-hydroxymitragynine (the alkaloids of Mitragyna speciosa Korth) on 4-methylumbelliferone glucuronidation in rat and human liver microsomes and recombinant human uridine 5’- diphospho-glucuronosyltransferase isoforms		Background: Glucuronidation catalyzed by uridine 5’- diphospho-glucuronosyltransferase (UGT) is a major phase II drug metabolism reaction which facilitates drug elimination. Inhibition of UGT activity can cause drug-drug interaction. Therefore, it is important to determine the inhibitory potentials of drugs on glucuronidation. Objective: The objective was to evaluate the inhibitory potentials of mitragynine, 7-hydroxymitragynine, ketamine and buprenorphine, respectively on 4-methylumbelliferone (4-MU) glucuronidation in rat liver microsomes, human liver microsomes and recombinant human UGT1A1 and UGT2B7 isoforms. Materials and Methods: The effects of the above four compounds on the formation of 4-MU glucuronide from 4-MU by rat liver microsomes, human liver microsomes, recombinant human UGT1A1 and UGT2B7 isoforms were determined using high-performance liquid chromatography with ultraviolet detection. Results: For rat liver microsomes, ketamine strongly inhibited 4-MU glucuronidation with an IC50 value of 6.21 ± 1.51 μM followed by buprenorphine with an IC50 value of 73.22 ± 1.63 μM. For human liver microsomes, buprenorphine strongly inhibited 4-MU glucuronidation with an IC50 value of 6.32 ± 1.39 μM. For human UGT1A1 isoform, 7-hydroxymitragynine strongly inhibited 4-MU glucuronidation with an IC50 value of 7.13 ± 1.16 μM. For human UGT2B7 isoform, buprenorphine strongly inhibited 4-MU glucuronidation followed by 7-hydroxymitragynine and ketamine with respective IC50 values of 5.14 ± 1.30, 26.44 ± 1.31, and 27.28 ± 1.18 μM. Conclusions: These data indicate the possibility of drug-drug interaction if 7-hydroxymitragynine, ketamine, and buprenorphine are co-administered with drugs that are UGT2B7 substrates since these three compounds showed significant inhibition on UGT2B7 activity. In addition, if 7-hydroxymitragynine is to be taken with other drugs that are highly metabolized by UGT1A1, there is a possibility of drug-drug interaction to occur.	26.692.748	2015485354	Centre for Drug Research	Universiti Sains Malaysia			Positive data entered	published	1	1	Published report
http://repo.napdi.org/NPDI-OYnBGA	166		Inhibition of CYP enzymes by glycyrrhetinic acid		The potential of licorice dietary supplements to interact with drug metabolism was evaluated by testing extracts of three botanically identified licorice species (Glycyrrhiza glabra L., Glycyrrhiza uralensis Fish. ex DC. and Glycyrrhiza inflata Batalin) and 14 isolated licorice compounds for inhibition of 9 cytochrome P450 enzymes using a UHPLC-MS/MS cocktail assay. G. glabra showed moderate inhibitory effects against CYP2B6, CYP2C8, CYP2C9, and CYP2C19, and weak inhibition against CYP3A4 (testosterone). In contrast, G. uralensis strongly inhibited CYP2B6 and moderately inhibited CYP2C8, CYP2C9 and CYP2C19, and G. inflata strongly inhibited CYP2C enzymes and moderately inhibited CYP1A2, CYP2B6, CYP2D6, and CYP3A4 (midazolam). The licorice compounds isoliquiritigenin, licoricidin, licochalcone A, 18β-glycyrrhetinic acid, and glycycoumarin inhibited one or more members of the CYP2C family of enzymes. Glycycoumarin and licochalcone A inhibited CYP1A2, but only glycycoumarin inhibited CYP2B6. Isoliquiritigenin, glabridin and licoricidin competitively inhibited CYP3A4, while licochalcone A (specific to G. inflata roots) was a mechanism-based inhibitor. The three licorice species commonly used in botanical dietary supplements have varying potential for drug-botanical interactions as inhibitors of cytochrome P450 isoforms. Each species of licorice displays a unique profile of constituents with potential for drug interactions.	28.774.812		UIC	UIC	22/03/2017 12:00 AM	30/07/2017 12:00 AM		published	1	1	Published report
http://repo.napdi.org/NPDI-twVQgQ	61	Goldenseal	Supplementation With Goldenseal (Hydrastis canadensis), but not Kava Kava (Piper methysticum), Inhibits Human CYP3A Activity In Vivo	PMID: 17495878	The effects of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on human CYP3A activity were evaluated using midazolam (MDZ) as a phenotypic probe. Sixteen healthy volunteers were randomly assigned to receive either goldenseal or kava kava for 14 days. Each supplementation phase was followed by a 30-day washout period. MDZ (8 mg, per os) was administered before and after each phase, and pharmacokinetic parameters were determined using standard non-compartmental methods. Comparisons of pre- and post-supplementation MDZ pharmacokinetic parameters revealed significant inhibition of CYP3A by goldenseal (AUC(0–N), 107.9743.3 vs 175.3774.8 ng x h/ml; Cl/F/kg, 1.2670.59 vs 0.8170.45 l/h/kg; T1/2, 2.0170.42 vs 3.1571.12 h; Cmax, 50.6726.9 vs 71.2750.5 ng/ml). MDZ disposition was not affected by kava kava supplementation. These findings suggest that significant herb–drug interactions may result from the concomitant ingestion of goldenseal and CYP3A substrates.	17.495.878		University of Arkansas for Medical Sciences	Department of Pharmaceutical Sciences				published	1	1	Published report
http://repo.napdi.org/NPDI-vA2ioQ	797	Cannabis	Hemp (high CBD) extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-hemp-high-CBD-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-eReNjw	169	Kratom	Exploration of cytochrome P450 inhibition mediated drug-drug interaction potential of kratom alkaloids		In vitro cytochrome P450 inhibition of major kratom alkaloids: mitragynine (MTG), speciogynine (SPG), speciocilliatine (SPC), corynantheidine (COR), 7-hydroxymitragynine (7HMG) and paynantheine (PAY) was evaluated using human liver microsomes (HLMs) to understand their drug-drug interaction potential. CYP450 isoform- specific substrates of CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4/5 were incubated in HLMs with or without alkaloids. Preliminary CYP450 inhibition (IC50) data were generated for each of these isoforms. In addition, the type of inhibition and estimation of the inhibition constants (Ki) of MTG and COR were determined. Among the tested alkaloids, MTG and COR were potent inhibitors of CYP2D6 (IC50, 2.2 and 4.2 μM, respectively). Both MTG and COR exhibited competitive inhibition of CYP2D6 activity and the Ki were found to be 1.1 and 2.8 μM, respectively. SPG and PAY showed moderate inhibition of CYP2D6 activity. Additionally, moderate inhibitory effects by SPC, MTG, and SPG were observed on CYP2C19 activity. Interestingly, inhibition of only midazolam hydroxylase CYP3A4/5 activity by COR, PAY, and MTG was observed while no inhibitory effect was observed when testosterone was used as a probe substrate. In conclusion, MTG and COR may lead to clinically significant adverse drug interactions upon coadministration of drugs that are substantially metabolized by CYP2D6.	31.707.106	2003905259	UF	University of Florida				published	1	1	Published report
http://repo.napdi.org/NPDI-6yhsoA	14	Green tea	Effects of repeated green tea catechin administration on human cytochrome P450 activity.	PMID:17164372	Based on the results, repeated green tea catechin administration is not likely to result in clinically significant effects on the disposition of drugs metabolized by CYP enzymes.	17.164.372		University of Arizona and National Cancer Institute	Arizona Cancer Center, University of Arizona; Division of Cancer Prevention, National Cancer Institute			This is a study reported in the literature. Data was entered by JY and reviewed by JS.	published	1	1	Published report
http://repo.napdi.org/NPDI-doKK2g	824	Valerian	Valerian root extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-valerian-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-8SkM4A	147	Licorice	Cytochrome P450 inhibition by licorice species Glycyrrhiza glabra L. and fourteen licorice constituents		The potential of licorice dietary supplements to interact with drug metabolism was evaluated by testing extracts of botanically identified licorice species Glycyrrhiza glabra L. and 14 isolated licorice compounds for inhibition of 9 cytochrome P450 enzymes using a UHPLC-MS/MS cocktail assay. G. glabra showed moderate inhibitory effects against CYP2B6, CYP2C8, CYP2C9, and CYP2C19, and weak inhibition against CYP3A4 (testosterone). The licorice compounds isoliquiritigenin, licoricidin, licochalcone A, 18β-glycyrrhetinic acid, and glycycoumarin inhibited one or more members of the CYP2C family of enzymes. Glycycoumarin and licochalcone A inhibited CYP1A2, but only glycycoumarin inhibited CYP2B6. Isoliquiritigenin, glabridin and licoricidin competitively inhibited CYP3A4. Licorice species commonly used in botanical dietary supplements have varying potential for drug-botanical interactions as inhibitors of cytochrome P450 isoforms. Each species of licorice displays a unique profile of constituents with potential for drug interactions.	28.774.812		UIC	UIC	22/03/2017 12:00 AM	30/07/2017 12:00 AM		published	1	1	Published report
http://repo.napdi.org/NPDI-lalKkg	787	Cannabis	Predicting the Potential for Cannabinoids to Precipitate Pharmacokinetic Drug Interactions via Reversible Inhibition or Inactivation of Major Cytochromes P450		Cannabis constituents, CBD and THC, have been known to inhibit or inactive CYP450 enzymes. The binding-corrected reversible (IC50,u) and irreversible inhibition potency (KI,u) values were determined for CBD and THC. A combined mechanistic static model showed a moderate-strong interaction between CBD and drugs metabolized via CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A. The model also showed an interaction between THC and CYP1A2, CYP2C9, and CYP3A.	32.587.099		UW-WSU-NaPDI	Department of Pharmaceutics, UW; Department of Pharmaceutical Sciences, WSU; NaPDI				published	1	1	Published report
http://repo.napdi.org/NPDI-qiyzaQ	157		Inhibition of CYP enzymes by licoricidin		The potential of licorice dietary supplements to interact with drug metabolism was evaluated by testing extracts of three botanically identified licorice species (Glycyrrhiza glabra L., Glycyrrhiza uralensis Fish. ex DC. and Glycyrrhiza inflata Batalin) and 14 isolated licorice compounds for inhibition of 9 cytochrome P450 enzymes using a UHPLC-MS/MS cocktail assay. G. glabra showed moderate inhibitory effects against CYP2B6, CYP2C8, CYP2C9, and CYP2C19, and weak inhibition against CYP3A4 (testosterone). In contrast, G. uralensis strongly inhibited CYP2B6 and moderately inhibited CYP2C8, CYP2C9 and CYP2C19, and G. inflata strongly inhibited CYP2C enzymes and moderately inhibited CYP1A2, CYP2B6, CYP2D6, and CYP3A4 (midazolam). The licorice compounds isoliquiritigenin, licoricidin, licochalcone A, 18β-glycyrrhetinic acid, and glycycoumarin inhibited one or more members of the CYP2C family of enzymes. Glycycoumarin and licochalcone A inhibited CYP1A2, but only glycycoumarin inhibited CYP2B6. Isoliquiritigenin, glabridin and licoricidin competitively inhibited CYP3A4, while licochalcone A (specific to G. inflata roots) was a mechanism-based inhibitor. The three licorice species commonly used in botanical dietary supplements have varying potential for drug-botanical interactions as inhibitors of cytochrome P450 isoforms. Each species of licorice displays a unique profile of constituents with potential for drug interactions.	28.774.812		UIC	UIC	22/03/2017 12:00 AM	30/07/2017 12:00 AM		published	1	1	Published report
http://repo.napdi.org/NPDI-BacmiQ	792	Guggul	Guggul oleo-gum resin extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-guggul-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-jCrpqg	150	Green tea	Green Tea Metabolomics					UNCG	University of North Carolina - Greensboro			Data entered by EC via data spreadsheets provided by UNCG.	published	3	3	Unpublished data submitted through a NaPDI form
http://repo.napdi.org/NPDI-9DI3Ew	808	Horsetail	Horsetail stem extract Nuclear Receptor Induction study - Ole Miss		PXR is a key regulator for the expression of CYP 3A4 which is involved in the metabolism of majority of clinical drugs. Induction of PXR has been known to be associated with pharmacokinetic drug interactions. AhR is involved in regulation of the expression of certain CYP isoforms. Phytochemicals could be the AhR agonists and induction of AhR could play a role in herb-drug interation.	36.017.806		NCNPR-PXR-AHR-horsetail-1	Natural Center for Natural Products Research				published	1	1	Published report
http://repo.napdi.org/NPDI-yBr48Q	63	Goldenseal	The Effects of Berberine on the Pharmacokinetics of Ciclosporin A in Healthy Volunteers	PMID: 16541194	The effects of berberine (BBR) on the pharmacokinetics of ciclosporin A (CsA) were examined in healthy volunteers. Six healthy male volunteers were orally treated with 0.3 g BBR, twice daily for 10 days. Pharmacokinetic investigations on CsA at 6 mg/kg were done both before and at the end of the BBR treatment period. Another six healthy male volunteers were involved in the pharmacokinetic study with 3 mg CsA/kg, in which the subjects orally received the second single dose of 3 mg CsA/kg, followed by a single oral dose of 0.3 g BBR. The blood CsA concentrations were determined by fluorescence polarization immunoassay. In the pharmacokinetic study with 6 mg CsA/kg, BBR caused no significant changes in the pharmacokinetic parameters of CsA. However, in the trial with 3 mg CsA/kg, the average percentage increase in area under the blood concentration-time curve of CsA was 19.2% (P < 0.05) and the mean C12 increased to 123 microg/l from 104 microg/l (P < 0.05), without altering elimination half-life (t(1/2)), maximum blood drug concentration (Cmax), time to Cmax (tmax), apparent oral clearance (CL/F). The present results suggest that BBR can increase the oral bioavailability of CsA at the dosage of 3 mg/kg. The BBR-mediated increase in CsA bioavailability may be partly attributed to a decrease in liver and/or intestinal metabolism through the inhibition of CYP3A4 in the liver and/or gut wall. The BBR-induced increase in emptying time of stomach and small intestine might be another reason for the increase in CsA bioavailability. However, the speculation should be proved by further investigation.	16.541.194		Wuhan General Hospital	Department of Clinical Pharmacology				published	1	1	Published report
http://repo.napdi.org/NPDI-osTXuQ	832	Kratom	Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom		Oral formulations prepared from the leaves of the kratom (Mitragyna speciosa) plant are increasingly used for their opioid-like effects to self-manage opioid withdrawal and pain. Calls to US poison centers involving kratom exposures increased >50-fold from 2011-2017, one-third of which reported concomitant use of kratom with drugs of abuse. Many of these drugs are eliminated primarily via cytochrome P450 (CYP) 3A and CYP2D6, raising concerns for potential adverse pharmacokinetic kratom-drug interactions. The impact of a single low dose of kratom tea (2 g) on the pharmacokinetics of the CYP3A probe midazolam (2.5 mg) and CYP2D6 probe dextromethorphan (30 mg) were assessed in 12 healthy adult participants after oral administration. Kratom showed no effect on dextromethorphan area under the plasma concentration time-curve (AUC) and maximum concentration (C_max ; geometric mean ratio (90% confidence interval) 0.99 (0.83-1.19) and 0.96 (0.78-1.19), respectively) but a modest increase in midazolam AUC and C_max (1.39 (1.23-1.57) and 1.50 (1.32-1.70), respectively). Lack of change in midazolam half-life (1.07 (0.98-1.17)) suggested that kratom primarily inhibited intestinal CYP3A. This inference was further supported by a physiologically based pharmacokinetic drug interaction model using the abundant alkaloid mitragynine, a relatively potent CYP3A time-dependent inhibitor in vitro (K_I , ~4 μM; k_inact , ~0.07 min^-1 ). This work is the first to clinically evaluate the pharmacokinetic drug interaction potential of kratom. Co-consuming kratom with certain drugs extensively metabolized by CYP3A may precipitate serious interactions. These data fill critical knowledge gaps about the safe use of this increasingly popular natural product, thereby addressing ongoing public health concerns.	36.924.284		WSU-pmid-35335999	Department of Pharmaceutical Sciences, Washington State University				published	1	1	Published report
http://repo.napdi.org/NPDI-VYyv-A	118	Cannabis	Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes	PMID: 20117100	Inhibitory effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), cannabidiol (CBD), and cannabinol (CBN), the three major constituents in marijuana, on catalytic activities of human cytochrome P450 (CYP) 1 enzymes were investigated. These cannabinoids inhibited 7-ethoxyresorufin O-deethylase activity of recombinant CYP1A1, CYP1A2, and CYP1B1 in a competitive manner. CBD most potently inhibited the CYP1A1 activity; the apparent K(i) value (0.155microM) was at least one-seventeenth of the values for other CYP1 isoforms. On the other hand, CBN more effectively decreased the activity of CYP1A2 and CYP1B1 (K(i)=0.0790 and 0.148microM, respectively) compared with CYP1A1 (K(i)=0.541microM). Delta(9)-THC less potently inhibited the CYP1 activity than CBD and CBN, and showed low selectivity against the CYP1 inhibition (K(i)=2.47-7.54microM). The preincubation of CBD resulted in a time- and concentration-dependent decrease in catalytic activity of all the recombinant CYP1 enzymes and human liver microsomes. Similarly, the preincubation of Delta(9)-THC or CBN caused a time- and concentration-dependent inhibition of recombinant CYP1A1. The inactivation of CYP1A1 by CBD indicated the highest k(inact)/K(I) value (540l/mmol/min) among the CYP1 enzyme sources tested. The inactivation of recombinant CYP1A1 and human liver microsomes by CBD required NADPH, was not influenced by dialysis and by glutathione, N-acetylcysteine, and superoxide dismutase as trapping agents. These results indicated that CBD and CBN showed CYP1 isoform-selective direct inhibition and that CBD was characterized as a potent mechanism-based inhibitor of human CYP1 enzymes, especially CYP1A1.	20.117.100		20117100	Hokuriku University				published	1	1	Published report
http://repo.napdi.org/NPDI-sUzV-g	88	Cannabis	Characterization of Human Hepatic and Extrahepatic UDP-Glucuronosyltransferase Enzymes Involved in the Metabolism of Classic Cannabinoids	PMID: 19339377	Tetrahydrocannabinol (Delta(9)-THC), the primary psychoactive ingredient in marijuana, is subject to cytochrome P450 oxidation and subsequent UDP-glucuronosyltransferase (UGT)-dependent glucuronidation. Many studies have shown that CYP2C9 and CYP3A4 are the primary enzymes responsible for these cytochrome P450-dependent oxidations, but little work has been done to characterize phase II metabolic pathways. In this study, we test the hypothesis that there are specific human UGTs responsible for classic cannabinoid metabolism. The activities of 12 human recombinant UGTs toward classic cannabinoids [cannabinol (CBN), cannabidiol (CBD), (-)-Delta(8)-THC, (-)-Delta(9)-THC, (+/-)-11-hydroxy-Delta(9)-THC (THC-OH), and (-)-11-nor-9-carboxy-Delta(9)-THC (THC-COOH)] were evaluated using high-performance liquid chromatography-tandem mass spectrometry and labeling assays. Despite activity by UGT1A1, 1A3, 1A8, 1A9, 1A10, and 2B7 toward CBN, CBD, THC-OH, and THC-COOH, only selected UGTs demonstrate sufficient activity for further characterization of steady-state kinetics. CBN was the most recognized substrate as evidenced by activities from hepatic UGT1A9 and extrahepatic UGT1A7, UGT1A8, and UGT1A10. These results may reflect the introduction of an aromatic ring to Delta(9)-THC, leading to favorable pi stacking with phenylalanines in the UGT active site. Likewise, oxidation of Delta(9)-THC to THC-OH results in UGT1A9 and UGT1A10 activity toward the cannabinoid. Further oxidation to THC-COOH surprisingly leads to a loss in metabolism by UGT1A9 and UGT1A10, while creating a substrate recognized by UGT1A1 and UGT1A3. The resulting glucuronide of THC-COOH is the main metabolite found in urine, and thus these hepatic enzymes play a critical role in the metabolic clearance of cannabinoids. Taken together, glucuronidation of cannabinoids depends on upstream processing including enzymes such as CYP2C9 and CYP3A4.	19.339.377		Departments of Biochemistry and Molecular Biology	University of Arkansas for Medical Sciences				published	1	1	Published report
http://repo.napdi.org/NPDI-_cMj4g	212	Cannabis	Warfarin dose adjustment required after cannabidiol initiation and titration		A case of a possible interaction between cannabidiol and warfarin is presented along with a brief overview of cytochrome enzymes involved in these drugs' metabolism.	33.016.308		Did Not State	y, University of Alabama at Birmingham Hospital, Birmingham, AL				published	4	4	Published Case Report
http://repo.napdi.org/NPDI-muoDdQ	144	Cannabis	Cannabis extract (CBD) Characterization of Material		Certificate of Analysis from U of Mississippi Product Code: 1101 on 10/30/2018			WSU	WSU			Data entered by CB with a COA provided by WSU.	published	3	3	Unpublished data submitted through a NaPDI form
http://repo.napdi.org/NPDI-aujB5A	7	Green tea	Effects of green tea catechins on cytochrome P450 2B6, 2C8, 2C19, 2D6 and 3A activities in human liver and intestinal microsomes	PMID:23268924	The effects of green tea catechins on the main drug-metabolizing enzymatic system, cytochrome P450 (CYP), have not been fully elucidated. The objective of the present study was to evaluate the effects of green tea extract (GTE, total catechins 86.5%, w/w) and (-)-epigallocatechin-3-gallate (EGCG) on the activities of CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A in vitro, using pooled human liver and intestinal microsomes. Bupropion hydroxylation, amodiaquine N-deethylation, (S)-mephenytoin 4'-hydroxylation, dextromethorphan O-demethylation and midazolam 1'-hydroxylation were assessed in the presence or absence of various concentrations of GTE and EGCG to test their effects on CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A activities, respectively. Each metabolite was quantified using UPLC/ESI-MS, and the inhibition kinetics of GTE and EGCG on CYP enzymes was analyzed. In human liver microsomes, IC50 values of GTE were 5.9, 4.5, 48.7, 25.1 and 13.8 µg/mL, for CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A, respectively. ECGC also inhibited these CYP isoforms with properties similar to those of GTE, and produced competitive inhibitions against CYP2B6 and CYP2C8, and noncompetitive inhibition against CYP3A. In human intestinal microsomes, IC50 values of GTE and EGCG for CYP3A were 18.4 µg/mL and 31.1 µM, respectively. EGCG moderately inhibited CYP3A activity in a noncompetitive manner. These results suggest that green tea catechins cause clinically relevant interactions with substrates for CYP2B6 and CYP2C8 in addition to CYP3A.	23.268.924		NA	University of Shizuoka, Japan			This is a study reported in the literature. The data was entered by JS and reviewed by JY.	published	1	1	Published report