CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid-dose concentration in HIV-infected patients

Awewura Kwara; Margaret Lartey; Kwamena W C Sagoe; Ernest Kenu; Michael H Court

doi:10.1097/QAD.0b013e3283319908

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CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid-dose concentration in HIV-infected patients

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CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid-dose concentration in HIV-infected patients

Awewura Kwara, Margaret Lartey, Kwamena W C Sagoe, Ernest Kenu and Michael H Court

AIDS (London), Vol.23(16), pp.2101-2106

10/23/2009

DOI: https://doi.org/10.1097/QAD.0b013e3283319908

Handle:

https://hdl.handle.net/2376/100440

PMCID: PMC2875867

PMID: 19779319

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https://doi.org/10.1097/QAD.0b013e3283319908View

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Abstract

HIV Infections - blood

Cytochrome P-450 CYP2A6

Predictive Value of Tests

Oxidoreductases, N-Demethylating - genetics

Reverse Transcriptase Inhibitors - blood

HIV Infections - genetics

Humans

Aryl Hydrocarbon Hydroxylases - genetics

Genotype

Male

Ghana

Dose-Response Relationship, Drug

Glucuronosyltransferase - genetics

Reverse Transcriptase Inhibitors - pharmacokinetics

Benzoxazines - pharmacokinetics

Adult

Benzoxazines - blood

Female

HIV Infections - drug therapy

Polymorphism, Single Nucleotide

African Continental Ancestry Group - genetics

Cytochrome P-450 CYP2B6

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. 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. 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. 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.

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Title: CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid-dose concentration in HIV-infected patients
Creators: Awewura Kwara - Warren Alpert Medical School of Brown University, Rhode Island, USA. akwara@lifespan.org
Margaret Lartey
Kwamena W C Sagoe
Ernest Kenu
Michael H Court
Publication Details: AIDS (London), Vol.23(16), pp.2101-2106
Academic Unit: Veterinary Clinical Sciences, Department of
Publisher: England
Grant note: P30 AI042853 / NIAID NIH HHS P30 AI050410 / NIAID NIH HHS R01GM061834 / NIGMS NIH HHS P30AI042853 / NIAID NIH HHS K23 AI071760-04 / NIAID NIH HHS K23 AI071760 / NIAID NIH HHS R01 GM061834 / NIGMS NIH HHS
Identifiers: 99900546657501842
Language: English
Resource Type: Journal article