体外“鸡尾酒法”研究5-羟基雷公藤内酯醇对人肝微粒体CYP450酶亚型的抑制

中国临床药理学与治疗学 ›› 2013, Vol. 18 ›› Issue (11): 1211-1218.

体外“鸡尾酒法”研究5-羟基雷公藤内酯醇对人肝微粒体CYP450酶亚型的抑制

刘海燕, 张乐多, 向志雄, 苗红

上海医药集团股份有限公司中央研究院,上海 201203

收稿日期:2012-11-28 修回日期:2013-10-09 出版日期:2013-11-26 发布日期:2013-11-22
作者简介:刘海燕,女,博士,研究方向:新药研发中药物代谢动力学筛选。Tel: 021-61871700-8180 E-mail: liuhy@pharm-sh.com.cn
基金资助:
新药创制重大专项(2009ZX09102 ):一类新药雷腾舒的临床前研究

Inhibition study of cytochrome P450 isozymes by (5R)-5-hydroxytriptolide using in vitro “cocktail” method

LIU Hai-yan, ZHANG Le-duo, XIANG Zhi-xiong, MIAO Hong

Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai 201203,China

Received:2012-11-28 Revised:2013-10-09 Online:2013-11-26 Published:2013-11-22

摘要/Abstract

摘要： 目的: 评价(5R)-5-羟基雷公藤内酯醇(T8)在体外对人肝微粒体CYP450酶7种主要亚型CYP3A/5、CYP2D6、CYP1A2、CYP2C9、CYP2C19、CYP2B6和CYP2C8的直接抑制作用和时间依赖性抑制作用,为临床药物-药物相互作用研究提供指导。方法: 本实验分别利用IC₅₀和IC₅₀ 偏移进行评价。结果: T8对上述7种亚型的直接抑制IC₅₀ 都高于 100 μmol/L,时间依赖性抑制研究中没有出现 IC₅₀ 偏移。结论: T8对7种主要的CYP450酶亚型没有直接抑制和时间依赖性抑制作用。临床上发生由于T8抑制上述7种亚型的CYP450酶导致的药物-药物相互作用的可能性较小。

关键词: 5-羟基雷公藤内酯醇, CYP450, 直接抑制, 时间依赖性抑制

Abstract: AIM: To evaluate whether 5-hydroxytriptolide (T8) is a direct inhibitior or time-dependent inhibitor of CYP3A/5, CYP2D6, CYP2C9, CYP1A2, CYP2C19, CYP2B6 and CYP2C8, and to evaluate the potential of drug-drug interaction with the substrates of above seven CYPs in clinical study, which provide a reference for clinical drug-drug interaction study.METHODS: IC₅₀ and IC₅₀ shift method were used in this study.RESULTS: The IC₅₀ of T8 on above seven CYPs was more than 100 μmol/L in direct inhibition experiment, and no IC₅₀ shift occurred in time-dependent inhibition experiment.CONCLUSION: T8 is neither a direct inhibitor nor time-dependent inhibitor of above seven CYPs, and the potential of drug-drug interaction caused by T8 inhibition on CYP450 isozymes is slim.

Key words: 5-hydroxytriptolide, CYP450, Direct inhibition, Time-dependent inhibition

中图分类号:

R965.2

刘海燕, 张乐多, 向志雄, 苗红. 体外“鸡尾酒法”研究5-羟基雷公藤内酯醇对人肝微粒体CYP450酶亚型的抑制[J]. 中国临床药理学与治疗学, 2013, 18(11): 1211-1218.

LIU Hai-yan, ZHANG Le-duo, XIANG Zhi-xiong, MIAO Hong. Inhibition study of cytochrome P450 isozymes by (5R)-5-hydroxytriptolide using in vitro “cocktail” method[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2013, 18(11): 1211-1218.

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