Anti-influenza prodrug oseltamivir is activated by carboxylesterase human carboxylesterase 1, and the activation is inhibited by antiplatelet agent clopidogrel
Anti-influenza prodrug oseltamivir is activated by carboxylesterase human carboxylesterase 1, and the activation is inhibited by antiplatelet agent clopidogrel
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DOI：
10.1124/jpet.106.111807
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发表时间：
2006-12-01
影响因子：
3.5
通讯作者：
Yan, Bingfang
中科院分区：
文献类型：
--
作者：
Shi, Deshi;Yang, Jian;Yan, Bingfang
奥司他韦是世界卫生组织为预防下一次流感大流行而推荐的主要药物。该抗流感病毒药物为酯类前药，通过其水解代谢产物奥司他韦羧酸盐实现抗病毒活性。在这项研究中，我们报告的水解活化催化羧酸酯酶人类羧酸酯酶（HCE）1。肝微粒体迅速水解奥司他韦，但肠微粒体或血浆中未检测到水解。水解的总体速率在个体肝脏样品中变化，并且与HCE 1水平良好相关。重组HCE1而不是HCE2水解该前药，并产生与肝微粒体相似的动力学参数。几种HCE1天然变体在奥司他韦的水解上与野生型酶不同。在抗血小板药氯吡格雷存在下，当测定等浓度时，奥司他韦的水解被抑制高达90%。考虑到奥司他韦的水解是其治疗活性所必需的事实，同时使用两种药物将抑制奥司他韦的活化，从而使这种抗病毒剂在治疗上无活性。这在流行病学上具有重要意义，因为同时接受奥司他韦和氯吡格雷的人可能会保持对流感感染的易感性，或者如果已经感染，则可能成为传播流感病毒的来源。
Oseltamivir is the main medicine recommended by the World Health Organization in anticipation of next influenza pandemic. This anti-influenza viral agent is an ester prodrug, and the antiviral activity is achieved by its hydrolytic metabolite: oseltamivir carboxylate. In this study, we report that the hydrolytic activation is catalyzed by carboxylesterase human carboxylesterase (HCE) 1. Liver microsomes rapidly hydrolyzed oseltamivir, but no hydrolysis was detected with intestinal microsomes or plasma. The overall rate of the hydrolysis varied among individual liver samples and was correlated well with the level of HCE1. Recombinant HCE1 but not HCE2 hydrolyzed this prodrug and produced similar kinetic parameters as the liver microsomes. Several HCE1 natural variants differed from the wildtype enzyme on the hydrolysis of oseltamivir. In the presence of antiplatelet agent clopidogrel, the hydrolysis of oseltamivir was inhibited by as much as 90% when the equal concentration was assayed. Given the fact that hydrolysis of oseltamivir is required for its therapeutic activity, concurrent use of both drugs would inhibit the activation of oseltamivir, thus making this antiviral agent therapeutically inactive. This is epidemiologically of significance because people who receive oseltamivir and clopidogrel simultaneously may maintain susceptibility to influenza infection or a source of spreading influenza virus if already infected.