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In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function.

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author di Iulio Julia, Fayet Aurélie, Arab-Alameddine Mona, Rotger Margalida, Lubomirov Rubin, Cavassini Matthias, Furrer Hansjakob, Günthard Huldrych F, Colombo Sara, Csajka Chantal, Eap Chin B, Decosterd Laurent A, Telenti Amalio, Swiss HIV Cohort Study,
Project Pharmacocinétique de population, pharmacogénétique, et profils métaboliques de la thérapie anti-HIV
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Original article (peer-reviewed)

Journal Pharmacogenetics and genomics
Volume (Issue) 19(4)
Page(s) 300 - 9
Title of proceedings Pharmacogenetics and genomics
DOI 10.1097/FPC.0b013e328328d577


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 2B6 (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.