In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function
In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function
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DOI：
10.1097/fpc.0b013e328328d577
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发表时间：
2009-04-01
影响因子：
2.6
通讯作者：
Telenti, Amalio
中科院分区：
文献类型：
--
作者：
di Iulio, Julia;Fayet, Aurelie;Telenti, Amalio
抗逆转录病毒药物依非韦伦（efavirenz， EFV）被广泛代谢为三种主要代谢物：8-羟基EFV、7-羟基EFV和n -葡萄糖醛酸苷EFV。EFV血浆暴露存在广泛的个体间差异，这在很大程度上是由细胞色素P450 2136 （CYP2B6）解释的，它是负责EFV代谢的主要同工酶，参与主要的代谢途径（8-羟基化），在较小程度上参与7-羟基化。当CYP2B6功能受损时，负责7-羟基化的主要同工酶CYP2A6的相关性可能会增加。我们假设该基因的遗传变异性可能导致CYP2B6功能有限的个体在EFV暴露中具有特别高的、无法解释的变异性。方法本研究对先前被鉴定为CYP2B6（18个等位基因）功能变异的个体（N=169）的CYP2A6变异（14个等位基因）进行了分析。测定体内不同遗传背景下EFV及其主要代谢物（8-羟基-EFV、7-羟基-EFV和n -葡萄糖醛酸-EFV）的血浆浓度。结果辅助代谢途径CYP2A6在CYP2B6慢代谢个体中具有限制药物积累的关键作用。结论CYP2B6和CYP2A6双重缓慢代谢在不同人群中发生频率显著，导致极高的EFV暴露。药物遗传学和基因组学19:300-309 (C) 2009 Wolters Kluwer Health垂直bar Lippincott Williams & Wilkins。
Introduction The antiretroviral drug efavirenz (EFV) is extensively metabolized into three primary metabolites: 8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV. There is a wide interindividual variability in EFV plasma exposure, explained to a great extent by cytochrome P450 2136 (CYP2B6), the main isoenzyme responsible for EFV metabolism and involved in the major metabolic pathway (8-hydroxylation) and to a lesser extent in 7-hydroxylation. When CYP2B6 function is impaired, the relevance of CYP2A6, the main isoenzyme responsible for 7-hydroxylation may increase. We hypothesize that genetic variability in this gene may contribute to the particularly high, unexplained variability in EFV exposure in individuals with limited CYP2B6 function.Methods This study characterized CYP2A6 variation (14 alleles) in individuals (N=169) previously characterized for functional variants in CYP2B6 (18 alleles). Plasma concentrations of EFV and its primary metabolites (8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV) were measured in different genetic backgrounds in vivo.Results The accessory metabolic pathway CYP2A6 has a critical role in limiting drug accumulation in individuals characterized as CYP2B6 slow metabolizers.Conclusion Dual CYP2B6 and CYP2A6 slow metabolism occurs at significant frequency in various human populations, leading to extremely high EFV exposure. Pharmacogenetics and Genomics 19:300-309 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.