In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function.
Iulio, Julia di a; Fayet, Aurelie b; Arab-Alameddine, Mona b; Rotger, Margalida a; Lubomirov, Rubin a; Cavassini, Matthias c; Furrer, Hansjakob e; Gunthard, Huldrych F. f; Colombo, Sara a; Csajka, Chantal b g; Eap, Chin B. d; Decosterd, Laurent A. b; Telenti, Amalio a; the Swiss HIV Cohort Study
Pharmacogenetics and Genomics.
19(4):300-309, April 2009.
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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.
(C) 2009 Lippincott Williams & Wilkins, Inc.