Interspecies variation of clopidogrel hydrolysis in liver microsomes from various mammals
Interspecies variation of clopidogrel hydrolysis in liver microsomes from various mammals
复制标题
不同哺乳动物肝微粒体中氯吡格雷水解的种间差异
DOI：
10.1016/j.cbi.2019.108871
复制
发表时间：
2020-01-05
影响因子：
5.1
通讯作者：
Tang, Hui
中科院分区：
文献类型：
--
作者：
Wang, Ya-Qiao;Shang, Xiao-Feng;Tang, Hui
氯吡格雷是一种临床使用的抗血小板药物，很容易被人羧酸酯酶1A（CES1A）水解，释放出无活性的代谢物氯吡格雷羧酸（CCA）。本研究以氯吡格雷为工具底物，研究了包括人类和六种实验动物（如小鼠、大鼠、兔、比格犬、小型猪和食蟹猴）在内的多种哺乳动物肝微粒体中氯吡格雷水解的种间差异。结果表明，所有测试的人类或其他哺乳动物的肝微粒体均可将氯吡格雷水解为CCA，但水解速率在物种之间差异很大。抑制测定表明，BNPP（哺乳动物 CES 的灭活剂）可强烈灭活所有测试的肝微粒体中的氯吡格雷水解活性，表明哺乳动物 CES 是所有上述物种的肝制剂中氯吡格雷水解的主要贡献者。相比之下，人类 CES1A 可逆抑制剂对这些肝脏制剂中氯吡格雷水解的反应在不同物种之间存在显着差异。此外，还评估并比较了不同动物物种肝微粒体中氯吡格雷水解的酶动力学和表观动力学参数。这些发现为深入了解哺乳动物CES催化行为的差异提供了重要信息，这对于选择合适的实验动物进行CES1A底物药物的整体测试非常有帮助。
Clopidogrel, a clinically used antiplatelet agent, can be readily hydrolyzed by human carboxylesterase 1A (CES1A) to release an inactive metabolite clopidogrel carboxylic acid (CCA). In this study, clopidogrel was used as a tool substrate to investigate the interspecies variation of clopidogrel hydrolysis in hepatic microsomes from various mammals including human and six laboratory animals (such as mouse, rat, rabbit, beagle dog, minipig and cynomolgus monkey). The results demonstrated that clopidogrel could be hydrolyzed into CCA by all tested hepatic microsomes from human or other mammals, but the hydrolytic rates greatly varied among species. Inhibition assays demonstrated that BNPP (an inactivator of mammalian CES) strongly inactivated clopidogrel hydrolytic activity in all tested hepatic microsomes, suggested that mammalian CES were major contributor(s) responsible for clopidogrel hydrolysis in hepatic preparations from all above-mentioned species. By contrast, the response of a reversible inhibitor of human CES1A on clopidogrel hydrolysis in these liver preparations varied significantly among different species. Moreover, the enzymatic kinetics and the apparent kinetic parameters of clopidogrel hydrolysis in hepatic microsomes from various animal species were evaluated and compared to each other. These findings provide crucial information for deeply understanding the differences in catalytic behaviors of mammalian CES, which will be very helpful for choosing suitable laboratory animal(s) for whole tests of CES1A substrate-drugs.