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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.

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.

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. 

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.

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.

• 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.
  

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.

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.

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.

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.

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.

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.

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.

1. 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.
2. 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.
3. 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.
4. 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.

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.

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).

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.

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.

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.