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

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 (2009). In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function. Pharmacogenetics and genomics, 19(4), pp. 300-9. London: Lippincott Williams & Wilkins 10.1097/FPC.0b013e328328d577

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Infectiology

UniBE Contributor:

Furrer, Hansjakob

ISSN:

1744-6872

Publisher:

Lippincott Williams & Wilkins

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:14

Last Modified:

04 May 2014 23:23

Publisher DOI:

10.1097/FPC.0b013e328328d577

PubMed ID:

19238117

Web of Science ID:

000264943900006

URI:

https://boris.unibe.ch/id/eprint/32456 (FactScience: 197664)

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