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

AIDS. 2009 Oct 23;23(16):2101-6. doi: 10.1097/QAD.0b013e3283319908.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • African Continental Ancestry Group / genetics
  • Alkynes
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Benzoxazines / blood*
  • Benzoxazines / pharmacokinetics
  • Cyclopropanes
  • Cytochrome P-450 CYP2A6
  • Cytochrome P-450 CYP2B6
  • Dose-Response Relationship, Drug
  • Female
  • Genotype
  • Ghana
  • Glucuronosyltransferase / genetics*
  • HIV Infections / blood
  • HIV Infections / drug therapy
  • HIV Infections / genetics*
  • Humans
  • Male
  • Oxidoreductases, N-Demethylating / genetics*
  • Polymorphism, Single Nucleotide
  • Predictive Value of Tests
  • Reverse Transcriptase Inhibitors / blood*
  • Reverse Transcriptase Inhibitors / pharmacokinetics

Substances

  • Alkynes
  • Benzoxazines
  • Cyclopropanes
  • Reverse Transcriptase Inhibitors
  • Aryl Hydrocarbon Hydroxylases
  • CYP2A6 protein, human
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2A6
  • Cytochrome P-450 CYP2B6
  • Oxidoreductases, N-Demethylating
  • UGT2B7 protein, human
  • Glucuronosyltransferase
  • efavirenz