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

Détails

ID Serval
serval:BIB_69748BF486BC
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function.
Périodique
Pharmacogenetics and Genomics
Auteur(s)
di Iulio J., Fayet A., Arab-Alameddine M., Rotger M., Lubomirov R., Cavassini M., Furrer H., Günthard H.F., Colombo S., Csajka C., Eap C.B., Decosterd L.A., Telenti A.
Collaborateur(s)
Swiss HIV Cohort Study
Contributeur(s)
Battegay M., Bernasconi E., Böni J., Bucher HC., Bürgisser P., Calmy A., Cattacin S., Cavassini M., Dubs R., Egger M., Elzi L., Fischer M., Flepp M., Fontana A., Francioli P., Furrer H., Fux C., Gorgievski M., Günthard H., Hirsch H., Hirschel B., Hösli I., Kahlert Ch., Kaiser L., Karrer U., Kind C., Klimkait T., Ledergerber B., Martinetti G., Martinez B., Müller N., Nadal D., Opravil M., Paccaud F., Pantaleo G., Rauch A., Regenass S., Rickenbach M., Rudin C., Schmid P., Schultze D., Schüpbach J., Speck R., Taffé P., Telenti A., Trkola A., Vernazza P., Weber R., Yerly S.
ISSN
1744-6872 (Print)
ISSN-L
1744-6872
Statut éditorial
Publié
Date de publication
2009
Peer-reviewed
Oui
Volume
19
Numéro
4
Pages
300-309
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
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.
Mots-clé
African Continental Ancestry Group/genetics, Alleles, Anti-HIV Agents/blood, Anti-HIV Agents/chemistry, Aryl Hydrocarbon Hydroxylases/metabolism, Asian Continental Ancestry Group/genetics, Benzoxazines/blood, Benzoxazines/chemistry, European Continental Ancestry Group/genetics, Gene Frequency, Genetic Variation, Hispanic Americans/genetics, Humans, Metabolic Networks and Pathways/genetics, Molecular Structure, Pharmacogenetics, Polymorphism, Single Nucleotide
Pubmed
Web of science
Création de la notice
05/03/2009 13:24
Dernière modification de la notice
20/08/2019 14:24
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