Abstract 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 (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.

中文翻译：

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使用新开发的 LC-MS/MS 技术探索卡塔叶（Catha edulis）咀嚼对大鼠抗血小板药物氯吡格雷药代动力学的影响

摘要 氯吡格雷 (CLOP) 在世界范围内广泛用于治疗心血管并发症。CLOP 在肝脏中被细胞色素 P450 酶高度代谢为其活性代谢物。研究表明，卡塔叶是一种令人上瘾的物质，是细胞色素 P450 酶的强大抑制剂，可以影响伴随使用的药物的代谢。因此，本研究旨在评估 khat 对大鼠 CLOP 药代动力学的影响。在这项研究中，大鼠单独服用 CLOP 或 CLOP 与 khat 组合，并在不同的时间间隔获取血浆，并使用新开发和验证的液相色谱串联质谱 (LC-MS/MS) 方法使用 foretinib (FTB) 进行分析) 作为内标。分析物相对于 FTB 的相应峰面积用于计算峰比。经验证的 LC-MS/MS 方法可在 7 分钟内分离出明确定义的 CLOP、FTB 和 CLOP 代谢物的可量化峰。结果显示 khat 对 CLOP 代谢物的峰值比率有显着影响，与单独使用 CLOP 相比，该比率显着降低（P < 0.05），表明由于抑制卡塔叶的 CYP450 酶。因此，可能需要对使用 CLOP 的普通卡塔叶咀嚼者进行剂量调整。结果显示 khat 对 CLOP 代谢物的峰值比率有显着影响，与单独使用 CLOP 相比，该比率显着降低（P < 0.05），表明由于抑制卡塔叶的 CYP450 酶。因此，可能需要对使用 CLOP 的普通卡塔叶咀嚼者进行剂量调整。结果显示 khat 对 CLOP 代谢物的峰值比率有显着影响，与单独使用 CLOP 相比，该比率显着降低（P < 0.05），表明由于抑制卡塔叶的 CYP450 酶。因此，可能需要对使用 CLOP 的普通卡塔叶咀嚼者进行剂量调整。