Journal
AIDS
Volume 23, Issue 16, Pages 2101-2106Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAD.0b013e3283319908
Keywords
CYP2A6; CYP2B6; efavirenz concentration; genetic polymorphisms; UGT2B7
Categories
Funding
- Lifespan/Tufts/Brown Center for AIDS Research [P30AI042853]
- NIH [AI071760]
- Doris Duke Foundation
- National Institute of General Medical Sciences (NIGMS), National Institutes of Health (Bethesda, Maryland, USA) [R01GM061834]
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Objective: UDP-glucuronosyltransferase (UGT) 2B7 was recently identified as the main enzyme mediating efavirenz N-glucuronidation. In this study, we determined whether selected UGT2B7 polymorphisms could be used to enhance the prediction of efavirenz plasma concentrations from CYP2B6 and CYP2A6 genotypes. Methods: Mid-dose efavirenz plasma concentrations were determined in 94 HIV-infected Ghanaian patients at 2-8 weeks of antiretroviral therapy. CYP2B6 and CYP2A6 genotypes had been previously reported. UGT2B7 exon 2 single-nucleotide polymorphisms (SNPs) c.735A>G (UGT2B7*1c; rs28365062) and c.802C>T (H268Y; UGT2B7*2; rs7439366) were determined by direct sequencing with UGT2B7*1a defined as the reference allele. Relationships between efavirenz plasma concentrations, demographic variables and genotypes were evaluated by univariate and multivariate statistical approaches. Results: The mean (+/- SD) mid-dose efavirenz plasma concentration was 3218 ( 3905) ng/ml with coefficient of variation of 121%. Independent predictors of efavirenz concentration included CYP2B6 c.516TT genotype (4030 ng/ml increase; 95% confidence interval 2882-5505 ng/ml, P<0.001), UGT2B7*1a carrier status (475 ng/ml increase; 95% confidence interval 138-899 ng/ml, P=0.004) and CYP2A6*9 and/or *17 carrier status (372 ng/ml increase; 95% confidence interval 74-742 ng/ml, P=0.013). Overall, CYP2B6 c.516TT genotype, UGT2B7*1a carrier status and CYP2A6*9 or *17 carrier status accounted for 45.2, 10.1 and 8.6% of the total variance, respectively. Conclusion: Our findings demonstrate independent effects of CYP2A6 and UGT2B7 genetic variation on efavirenz disposition beyond that of the CYP2B6 polymorphisms. The development and testing of a pharmacogenetic algorithm for estimating the appropriate dose of efavirenz should incorporate genotypic data from both the oxidative and glucuronidation pathways. (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
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