Abstract
AbstractClopidogrel (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 (P < 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.
Highlights
Khat (Catha edulis [Vahl] Endl) is a plant that is grown in some parts of the South Western Arab Peninsula and East Africa [1]
We developed a sensitive, rapid, and robust liquid chromatography with tandem mass spectrometry (LC-MS/MS) technique to quantify CLOP in plasma samples using FTB (GSK1363089), which is a cytochrome P450 (CYP450)-3A subfamily substrate as International Standard (IS) to investigate the potential effect of khat on pharmacokinetics of CLOP and its metabolite
Various parameters used for the validation of the newly proposed LC-MS/MS method for CLOP assay were per the guidelines provided by Food and Drug Administration [21]
Summary
Khat (Catha edulis [Vahl] Endl) is a plant that is grown in some parts of the South Western Arab Peninsula and East Africa [1]. The leaves of the khat plant are chewed on a daily basis by more than 20 million people in the South Western Arabian Peninsula and Eastern part of Africa [2,3]. A large number of people chew khat leaves owing to their amphetamine-like properties with a variety of pleasurable and stimulating effects [4]. The stimulating and euphoric effects of khat are due to the presence of alkaloids, cathine and cathinone [5,6] These alkaloids are categorized as sympathomimetic amines, the category similar to amphetamine [7,8]. A number of studies have been carried out to establish the effects of khat on the cytochrome P450 (CYP450) enzyme family [9,10,11]. The khat extract was observed to inhibit all three subenzymes with IC50 of 42, 62, and 18 μg/mL, whereas cathinone showed negligible inhibition of the tested CYPs [12]
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