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


CONCLUSIONS
Dual CYP2B6 and CYP2A6 slow metabolism occurs at significant frequency in various human populations, leading to extremely high EFV exposure.
di Iulio
Julia
J
Institute of Microbiology Division of Clinical Pharmacology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.
Fayet
Aurélie
A
Arab-Alameddine
Mona
M
Rotger
Margalida
M
Lubomirov
Rubin
R
Cavassini
Matthias
M
Furrer
Hansjakob
H
Günthard
Huldrych F
HF
Colombo
Sara
S
Csajka
Chantal
C
Eap
Chin B
CB
Decosterd
Laurent A
LA
Telenti
Amalio
A
D000480:Alkynes; D000483:Alleles; D019380:Anti-HIV Agents / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D044466:Asian People / Q000235:genetics; D048588:Benzoxazines / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D044383:Black People / Q000235:genetics; D003521:Cyclopropanes; D065637:Cytochrome P-450 CYP2A6; D005787:Gene Frequency; D014644:Genetic Variation; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D015394:Molecular Structure; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; C098320:efavirenz