Minor contribution of CYP3A5 to the metabolism of hepatitis C protease inhibitor paritaprevir in vitro
Minor contribution of CYP3A5 to the metabolism of hepatitis C protease inhibitor paritaprevir in vitro
复制标题
CYP3A5 对丙型肝炎蛋白酶抑制剂帕立瑞韦体外代谢的贡献较小
DOI：
10.1080/00498254.2018.1524947
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发表时间：
2018
期刊：
影响因子：
1.8
通讯作者：
and Harumi Yamada
中科院分区：
文献类型：
--
作者：
Su Nwe San;Jun Matsumoto;Yumi Saito;Masako Koike;Hiroaki Sakaue;Yoshinori Kato;Masachika Fujiyoshi;Noritaka Ariyoshi;and Harumi Yamada
Paritaprevir（PTV）是一种非结构蛋白3/4A蛋白酶抑制剂，与奥比他韦（Obitasvir，OBV）和利托那韦（ritonavir，RTV）合用治疗丙型肝炎（Hepatitis C Disease，HCV）。本研究旨在利用人重组细胞色素P450（CYP 3A 4）、CYP 3A 5（rCYP 3A 4，rCYP 3A 5）和人肝微粒体（HLM）基因分型为CYP 3A 5 *1/*1，CYP 3A 5 *1/* 3或CYP 3A 5 *3/* 3。rCYP 3A 4对PTV代谢产物的固有清除率（克林特，Vmax/Km）是rCYP 3A 5的1.5倍。表达CYP 3A 5的CYP 3A 5 *1/* 1和CYP 3A 5 *1/* 3 HLM的PTV代谢与不表达CYP 3A 5的CYP 3A 5 *3/* 3 HLM相当。而CYP 3A 5表达水平与PTV代谢无明显相关性，提示参与PTV代谢的主要亚型是CYP 3A 4，而CYP 3A 5在PTV代谢中的作用较小。本研究的结果可能提供PTV代谢的基础信息，并可能进一步支持HCV感染患者处方PTV为基础的治疗的剂量实践。
Paritaprevir (PTV) is a non-structural protein 3/4A protease inhibitor developed for the treatment of hepatitis C disease as a fixed dose combination of ombitasvir (OBV) and ritonavir (RTV) with or without dasabuvir.The aim of this study was to evaluate the effects of cytochrome P450 (CYP) 3A5 onin vitroPTV metabolism using human recombinant CYP3A4, CYP3A5 (rCYP3A4, rCYP3A5) and human liver microsomes (HLMs) genotyped as eitherCYP3A5*1/*1,CYP3A5*1/*3orCYP3A5*3/*3.The intrinsic clearance (CLint,Vmax/Km) for the production of a metabolite from PTV in rCYP3A4 was 1.5 times higher than that in rCYP3A5. The PTV metabolism inCYP3A5*1/*1andCYP3A5*1/*3HLMs expressing CYP3A5 was comparable to that inCYP3A5*3/*3HLMs, which lack CYP3A5.CYP3A4 expression level was significantly correlated with PTV disappearance rate and metabolite formation. In contrast, there was no such correlation found for CYP3A5 expression level.This study represents that the major CYP isoform involved in PTV metabolism is CYP3A4, with CYP3A5 having a minor role in PTV metabolism. The findings of the present study may provide foundational information on PTV metabolism, and may further support dosing practices in HCV-infected patients prescribed PTV-based therapy.