Species Differences in Mechanism-Based Inactivation of CYP3A in Humans, Rats and Mice
Species Differences in Mechanism-Based Inactivation of CYP3A in Humans, Rats and Mice
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DOI：
10.2133/dmpk.25.93
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发表时间：
2010-01-01
影响因子：
2.1
通讯作者：
Chiba, Kan
中科院分区：
文献类型：
--
作者：
Aueviriyavit, Sasitorn;Kobayashi, Kaoru;Chiba, Kan
细胞色素P450 3A（CYP 3A）的机制失活（MBI）常引起严重的药物相互作用。为了研究人类和啮齿类动物之间CYP 3A MBI的物种差异，我们比较了五种代表性CYP 3A抑制剂在人类，大鼠和小鼠肝微粒体中的MBI效力。在研究的抑制剂中，红霉素和克拉霉素对大鼠和小鼠肝微粒体中CYP 3A活性的MBI效应明显弱于人肝微粒体。光谱实验结果表明，红霉素和克拉霉素与人肝微粒体形成代谢中间体复合物，但与大鼠或小鼠肝微粒体不形成。相比之下，醋竹桃霉素，地尔硫卓和尼卡地平与大鼠和小鼠肝微粒体形成代谢中间体复合物，尽管观察到种属间MBI效价存在一些差异。MBI效价（k（inact）/K-I比值）和可逆抑制（IC 50）参数呈负相关（r=-0.820，p=0.0003），表明CYP 3A抑制剂对CYP 3A的不同亲和力可能部分导致了种属间抑制剂MBI效价的差异。综上所述，这些结果表明，在人类、大鼠和小鼠中，CYP 3A的MBI存在种属差异，当将啮齿动物用作MBI介导的药物-药物相互作用研究的体内模型时，应考虑到这一点。
Mechanism-based inactivation (MBI) of cytochrome P450 3A (CYP3A) often causes serious drug-drug interactions. To examine species differences in MBI of CYP3A between humans and rodents, we compared MBI potencies of five representative CYP3A inhibitors in human, rat and mouse liver microsomes. Among the inhibitors studied, erythromycin and clarithromycin exhibited markedly weaker MBI effects on CYP3A activity in rat and mouse liver microsomes compared to human liver microsomes. Results of spectroscopic experiments showed that erythromycin and clarithromycin form a metabolic intermediate complex with human liver microsomes but not with rat or mouse liver microsomes. In contrast, troleandomycin, diltiazem and nicardipine form a metabolic intermediate complex with rat and mouse liver microsomes, although some differences in MBI potency among species were observed. Parameters for MBI potency (k(inact)/K-I ratio) and reversible inhibition (IC50) were negatively correlated (r=-0.820, p=0.0003), suggesting that the different affinities of CYP3A inhibitor for CYP3A may partly contribute to the different MBI potencies of inhibitor among species. Taken together, the results suggest that there are species differences in MBI of CYP3A in humans, rats and mice, which should be considered when rodents are used as in vivo models for MBI-mediated drug-drug interaction study.