Time-dependent inhibition of CYP3A4 by sertraline, a selective serotonin reuptake inhibitor
Time-dependent inhibition of CYP3A4 by sertraline, a selective serotonin reuptake inhibitor
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DOI：
10.1002/bdd.1857
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发表时间：
2013-11-01
影响因子：
2.1
通讯作者：
Kawaguchi, Yuki
中科院分区：
文献类型：
--
作者：
Masubuchi, Yasuhiro;Kawaguchi, Yuki
与选择性5-羟色胺再摄取抑制剂（SSRIs）相关的药物相互作用是众所周知的。SSRIs的主要相互作用是抑制细胞色素P450（P450）介导的肝脏药物代谢。据报道，SSRI（舍曲林）也会增加联合用药的血液浓度。舍曲林直接抑制肝脏药物代谢的效力与其他SSRIs相比相对较弱，这意味着相互作用中涉及其他机制。该研究检查舍曲林是否对CYP 3A 4和/或其他P450酶产生时间依赖性抑制。在存在NADPH的情况下，人肝微粒体与舍曲林孵育导致睾酮6-羟基化活性显著降低，表明舍曲林代谢导致CYP 3A 4失活。这种失活需要NADPH，并且不受谷胱甘肽的保护。未观察到其他P450酶的显著失活。光谱评价显示，在NADPH存在下，含和不含舍曲林的微粒体在455 nm处产生Soret峰，表明舍曲林代谢物与还原型P450形成代谢中间体（MI）复合物。这是首次报道舍曲林对CYP 3A 4产生时间依赖性抑制，可能与MI复合物的形成有关。版权所有（c）2013约翰威利父子有限公司
Drug-drug interactions associated with selective serotonin reuptake inhibitors (SSRIs) are widely known. A major interaction by SSRIs is the inhibition of cytochrome P450 (P450)-mediated hepatic drug metabolism. The SSRI, sertraline, is also reported to increase the blood concentration of co-administered drugs. The potency of sertraline directly to inhibit hepatic drug metabolism is relatively weak compared with the other SSRIs, implying that additional mechanisms are involved in the interactions. The study examined whether sertraline produces time-dependent inhibition of CYP3A4 and/or other P450 enzymes. Incubation of human liver microsomes with sertraline in the presence of NADPH resulted in marked decreases in testosterone 6-hydroxylation activities, indicating that sertraline metabolism leads to CYP3A4 inactivation. This inactivation required NADPH and was not protected by glutathione. No significant inactivation was observed for other P450 enzymes. Spectroscopic evaluation revealed that microsomes with and without sertraline in the presence of NADPH gave a Soret peak at 455 nm, suggesting the formation of metabolic intermediate (MI) complexes of sertraline metabolite(s) with the reduced form of P450. This is the first report indicating that sertraline produced time-dependent inhibition of CYP3A4, which may be associated with MI complex formation. Copyright (c) 2013 John Wiley & Sons, Ltd.