维罗非尼对UGT1A1介导的伊立替康代谢的抑制作用研究

doi:10.12092/j.issn.1009-2501.2019.07.008

中国临床药理学与治疗学 ›› 2019, Vol. 24 ›› Issue (7): 773-777.doi: 10.12092/j.issn.1009-2501.2019.07.008

维罗非尼对UGT1A1介导的伊立替康代谢的抑制作用研究

温纯洁¹，张颖²，吴兰香¹，周宏灏^1,3

¹重庆医科大学生命科学研究院，重庆 400016；²中国中医科学院西苑医院基础医学研究所，中药药理北京市重点实验室，北京 100091； ³中南大学湘雅医学院临床药理研究所，长沙 410078，湖南

收稿日期:2018-12-14 修回日期:2019-04-25 出版日期:2019-07-26 发布日期:2019-07-29
通讯作者: 吴兰香，女，博士，副研究员，研究方向：临床药理学。 Tel: 023-68480036 E-mail: lxwu@cqmu.edu.cn
作者简介:温纯洁，女，博士，助理研究员，研究方向：临床药理学。 Tel: 023-68480036 E-mail: wenchunj@cqmu.edu.cn
基金资助:
重庆市渝中区科技计划项目（20130127）；重庆市卫生局医学科研计划项目（2013-2-150）

Inhibitory effect of vemurafenib on UGT1A1-mediated irinotecan metabolism

WEN Chunjie¹, ZHANG Ying², WU Lanxiang ¹, ZHOU Honghao ^1,3

¹ Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China; ² Institute of Basic Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing Key Laboratory of Traditional Chinese Medicine Pharmacology, Beijing 100091, China; ³ Institute of Clinical Pharmacology, Xiangya Medical College of Central South University, Changsha 410078, Hunan，China

Received:2018-12-14 Revised:2019-04-25 Online:2019-07-26 Published:2019-07-29

摘要/Abstract

摘要：

目的:应用体外人肝微粒体及重组人源代谢酶孵育体系观察维罗非尼对尿苷二磷酸葡萄糖醛酸基转移酶1A1（UDP-glucuronosyltransferases,UGT1A1）介导的伊立替康代谢的抑制作用，通过体外-体内外推（in vitro-in vivo extrapolation,IV-IVE）预测体内药物-药物相互作用（drug-drug interaction,DDI）的发生风险。方法:以混合人肝微粒体（human liver microsomes,HLMs）及重组表达的人UGT1A1 作为酶源，观察维罗非尼对UGT1A1介导的伊立替康活性代谢产物SN-38葡糖醛酸化反应的抑制作用，求得半数最大抑制浓度（half maximum inhibitory concentration,IC50）和抑制动力学常数Ki及抑制类型；并基于体外参数预测了体内维罗非尼与伊立替康联合应用引发的潜在DDI风险。结果:维罗非尼对UGT1A1具有较强的非竞争性抑制作用，IC50 为4.35 μmol/L，Ki为9.77 μmol/L。口服治疗剂量的维罗非尼（960 mg，每日两次）可导致SN-38的药时曲线下面积（area under the curve,AUC）增加7%～149% 。结论:维罗非尼与伊立替康联合应用时，可通过强效抑制UGT1A1而影响伊立替康在体内的代谢清除，具有引发DDI的风险。

关键词: 维罗非尼, 伊立替康, 尿苷二磷酸葡萄糖醛酸基转移酶1A1, 药物-药物相互作用

Abstract:

AIM: To study the inhibitory effect of vemurafenib on UDP-glucuronosyltransferases 1A1 (UGT1A1)-mediated irinotecan metabolism, and predict the risk of drug-drug interactions (DDI) by in vitro-in vivo extrapolation (IV-IVE). METHODS: A panel of human liver microsomes (HLMs) and recombinant human UGT1A1 were used to characterize the inhibitory effect of vemurafenib on human UGT1A1-mediated glucuronidation of SN-38, the active metabolite of irinotecan. The half maximum inhibitory concentration (IC50) and the constant of inhibition kinetics (Ki) were obtained, and the potential risk of DDI was predicted based on in vitro parameters. RESULTS:Vemurafenib had strong non-competitive inhibitory effect on UGT1A1, the IC50 value was 4.35 μmol/L, and the inhibition kinetic constant Ki value was 9.77 μmol/L. The area under the curve (AUC) ratio of SN-38 can be increased by 7% to 149% at the oral dose of 960 mg twice daily. CONCLUSION: The strong inhibition of vemurafenib on UGT1A1 leads to reduction of the UGT1A1-mediated irinotecan metabolism, and increases the risk of DDI.

Key words: vemurafenib, irinotecan, UDP-glucuronosyltransferase 1A1, drug-drug interaction

中图分类号:

R28
R965.5

温纯洁，张颖，吴兰香，周宏灏. 维罗非尼对UGT1A1介导的伊立替康代谢的抑制作用研究[J]. 中国临床药理学与治疗学, 2019, 24(7): 773-777.

WEN Chunjie, ZHANG Ying, WU Lanxiang, ZHOU Honghao. Inhibitory effect of vemurafenib on UGT1A1-mediated irinotecan metabolism[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(7): 773-777.

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维罗非尼对UGT1A1介导的伊立替康代谢的抑制作用研究

Inhibitory effect of vemurafenib on UGT1A1-mediated irinotecan metabolism

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