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

Abstract

<jats:title>Abstract</jats:title><jats:p>Clopidogrel (CLOP) is widely used worldwide for cardiovascular complications. CLOP is highly metabolized in the liver to its active metabolite by cytochrome P450 enzymes. Studies have shown that khat, an addictive substance, is a powerful inhibitor of cytochrome P450 enzymes and can influence the metabolism of drugs that are concomitantly used. Therefore, this study was designed to evaluate the effects of khat on the pharmacokinetics of CLOP in rats. In this study, rats were administered either CLOP alone or CLOP combined with khat and their plasma were obtained at different time intervals and analyzed using the newly developed and validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method using foretinib (FTB) as the internal standard. The corresponding peak area of the analyte versus FTB was used for calculating the peak ratio. The validated LC-MS/MS method resulted in the separation of the well-defined quantifiable peaks of CLOP, FTB, and CLOP metabolite within 7 min. Results showed a significant influence of khat on the peak ratio of CLOP metabolite, which was found to be significantly decreased (<jats:italic>P</jats:italic> &lt; 0.05) in comparison to CLOP alone, suggesting significant decrease in the conversion of CLOP to its active metabolite due to the inhibition of CYP450 enzymes by khat. Therefore, there might be a need for dose adjustment for regular khat chewers using CLOP.</jats:p>

In vitro and In silico studies of interactions of cathinone with human recombinant cytochrome P450 CYP(1A2), CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2, and CYP3A5

“…Based on our findings, CYP inhibition by khat extracts could be caused by the many alkaloids present in khat as aforementioned, and could also be a combination of the major constituents in khat, namely cathinone and cathine, or with a mix of other constituents. A recent study using LC-MS/MS method to explore the effect of khat on pharmacokinetics of an antiplatelet drug, clopidogrel, in rats also substantiated our previous findings that herb-drug interactions should be taken into consideration during prescribing to ensure an optimal dosage of drugs such as clopidogrel [7] .…”

“…mephedrone) accompanied with alcohol [49] and co-abuse of controlled drugs such as heroin, cocaine, cannabis, ketamine and MDMA are popular among users [26] . Moreover, the concurrent polysubstance use among khat chewers are alcohols, cigarettes [47] , cardiovascular drugs [7] , cannabis, and benzodiazepine tablets, just to name a few [46] . Khat chewing reduces the bioavailability of co-administered antibiotics and antimalarial drugs, counteract with antihypertensive, antiarrhythmic and local anaesthetics but enhanced the effects of monoamine oxidase inhibitors and amphetamine like drugs [1] .…”

Protein-Ligand Identification andIn VitroInhibitory Effects of Cathine on 11 Major Human Drug Metabolizing Cytochrome P450s

“…35 An in vivo study using rats found that rats treated with both khat plus clopidogrel had significantly lower clopidogrel metabolite produced due to inhibition of CYP enzyme by khat. 36 These studies supported that khat inhibited CYP activities but did not make any investigations on the specific compounds in khat that contributed to the CYPs inhibition. Therefore, it is plain to see that ingredients other than cathinone such as cathine and norephedrine, for instance, could be involved in the CYP inhibitory effects of khat.…”

Khat-drug interactions: A systematic review

“…This finding suggested that constituents of khat attenuate the antiplatelet aggregating properties of aspi-rin, and thereby neutralize the beneficial actions of aspirin (Alkadi et al, 2008). Alhazmi et al, 2020, reported a significant influence of khat on the peak ratio of clopidogrel (CLOP) metabolite, which was found to be significantly decreased in comparison to CLOP alone, suggesting a significant decrease in the conversion of CLOP to its active metabolite due to the inhibition of CYP450 enzymes by khat. Therefore, there might be a need for dose adjustment for regular khat chewers using CLOP.…”