Effects of Khat (Catha edulis) use on catalytic activities of major drug-metabolizing cytochrome P450 enzymes and implication of pharmacogenetic variations

Abstract

In a one-way cross-over study, we investigated the effect of Khat, a natural amphetamine-like psychostimulant plant, on catalytic activities of five major drug-metabolizing cytochrome P450 (CYP) enzymes. After a one-week Khat abstinence, 63 Ethiopian male volunteers were phenotyped using cocktail probe drugs (caffeine, losartan, dextromethorphan, omeprazole). Phenotyping was repeated after a one-week daily use of 400 g fresh Khat leaves. Genotyping for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A5 were done. Urinary cathinone and phenylpropanolamine, and plasma probe drugs and metabolites concentrations were quantified using LC-MS/MS. Effect of Khat on enzyme activities was evaluated by comparing caffeine/paraxanthine (CYP1A2), losartan/losartan carboxylic acid (CYP2C9), omeprazole/5-hydroxyomeprazole (CYP2C19), dextromethorphan/dextrorphan (CYP2D6) and dextromethorphan/3-methoxymorphinan (CYP3A4) metabolic ratios (MR) before and after Khat use. Wilcoxon-matched-pair-test indicated a significant increase in median CYP2D6 MR (41%, p < 0.0001), and a marginal increase in CYP3A4 and CYP2C19 MR by Khat. Repeated measure ANOVA indicated the impact of CYP1A2 and CYP2C19 genotype on Khat-CYP enzyme interactions. The median MR increased by 35% in CYP1A2*1/*1 (p = 0.07) and by 40% in carriers of defective CYP2C19 alleles (p = 0.03). Urinary log cathinone/phenylpropanolamine ratios significantly correlated with CYP2D6 genotype (p = 0.004) and CYP2D6 MR (P = 0.025). Khat significantly inhibits CYP2D6, marginally inhibits CYP3A4, and genotype-dependently inhibit CYP2C19 and CYP1A2 enzyme activities.

Barriers to Implementing Clinical Pharmacogenetics Testing in Sub-Saharan Africa. A Critical Review

“…Phenoconversion is most likely to influence PGx results in African populations due to complex health interventions that include herbal medicines, although some enzymes such as CYP2D6 are not easily induced. Khat ( Catha edulis Forsk ), a psychoactive herb commonly used in East Africa, has been identified as a potent inhibitor of the CYP2D6 enzyme (which metabolises up to 25% of prescribed medications) [ 66 ]. Therefore, environmental factors such as regional lifestyles and co-medication should be considered in future studies and in the interpretation of clinical pharmacogenetically guided drug prescription.…”

Exploring the effect of khat (Catha edulis) chewing on the pharmacokinetics of the antiplatelet drug clopidogrel in rats using the newly developed LC-MS/MS technique

“…They result in the feeling of well-being and mental alertness as well as excitement in users, but they have a number of untoward effects as well, which is why their use is banned in many countries. As aforementioned, the previous research shows neither cathine nor cathinone appears to be responsible for the inhibition of cytochrome subenzymes [9,10,12,28]. Therefore, investigating the molecular mechanism of cytochrome subenzymes' inhibition by khat is still very much needed.…”

“…Previously, a number of studies have been carried out to establish the effects of khat on the cytochrome P450 (CYP450) enzyme family [9][10][11]. In one of these studies, the effects of the khat extract on the activity of three in vitro human recombinant cytochrome P450 (CYP)2C9, CYP2D6, and CYP3A4 enzymes were checked and compared with that of cathinone, a constituent of khat [12].…”

Direct‐acting antiviral interactions with opioids, alcohol or illicit drugs of abuse in HCV‐infected patients

“…57 A study in healthy users of khat showed that the use of this plant resulted in a CYP2D6 inhibition and a marginal effect on CYP3A4 and CYP2C19 activities, owing to competitive inhibition by cathinone. 58 Potential interactions between cathinones and DAA are limited.…”