Key Laboratory for Molecular Enzymology & Engineering of the Ministry of Education, Jilin University, Changchun, China.
School of Life Sciences, Jilin University, Changchun, China.
Biopharm Drug Dispos. 2023 Apr;44(2):129-136. doi: 10.1002/bdd.2349. Epub 2023 Mar 11.
Clopidogrel (Clop) is oxidized by cytochrome P450s (CYPs) to an active thiol metabolite, Clop-AM, to inhibit platelet activation and aggregation. As an irreversible inhibitor of CYP2B6 and CYP2C19, clopidogrel may inhibit its own metabolism after long-term administration. The study compared the pharmacokinetic profiles of clopidogrel and its metabolites in rats receiving a single or a 2 week administration of Clop. The mRNA and protein levels of hepatic clopidogrel-metabolizing enzymes and their enzymatic activities were analyzed to explore their contribution to any altered plasma exposure of Clop and its metabolites. The results showed that long-term treatment with clopidogrel significantly decreased the AUC and C values of Clop-AM in rats, accompanied with markedly impaired catalytic activities of Clop-metabolizing CYPs including CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4. It suggests that consecutive administration of Clop to rats decreases hepatic CYPs activities, which may, in turn, inhibit clopidogrel metabolism and then reduce Clop-AM plasma exposure. Therefore, long-term treatment with clopidogrel has the potential to reduce its anti-platelet activity and to increase the risk of drug-drug interaction.
氯吡格雷（Clop）被细胞色素 P450 （CYPs）氧化为活性硫醇代谢物 Clop-AM，以抑制血小板激活和聚集。作为 CYP2B6 和 CYP2C19 的不可逆抑制剂，氯吡格雷在长期给药后可能会抑制自身的代谢。本研究比较了单次和 2 周给予氯吡格雷后大鼠体内氯吡格雷及其代谢物的药代动力学特征。分析肝内氯吡格雷代谢酶的 mRNA 和蛋白水平及其酶活性，以探讨其对氯吡格雷及其代谢物血浆暴露改变的贡献。结果表明，长期给予氯吡格雷治疗可显著降低大鼠体内 Clop-AM 的 AUC 和 C 值，同时显著降低氯吡格雷代谢相关 CYP 的催化活性，包括 CYP1A2、CYP2B6、CYP2C9、CYP2C19 和 CYP3A4。这表明连续给予氯吡格雷治疗可降低肝 CYP 活性，进而抑制氯吡格雷代谢，从而降低 Clop-AM 的血浆暴露。因此，长期给予氯吡格雷治疗可能会降低其抗血小板活性，并增加药物相互作用的风险。
