title: Associations between ABCB1, CYP2A6, CYP2B6, CYP2D6, and CYP3A5 alleles in relation to efavirenz and nevirapine pharmacokinetics in HIV-infected individuals.
abstract: BACKGROUND
  Human immunodeficiency virus (HIV)-infected individuals show large interindividual variation in response to antiretroviral therapy. Efavirenz (EFV) and nevirapine (NVP) are nonnucleoside reverse transcriptase inhibitors, which are prescribed in combination with other antiretroviral therapy in so-called highly active antiretroviral therapy. Recent studies provide evidence for the role of cytochrome P450 (CYP) genes, in particular CYP2B6, in relation to EFV and NVP pharmacokinetics. In this study, the authors investigated whether common ABCB1, CYP2A6, CYP2B6, CYP2D6, and CYP3A5 alleles are associated with plasma concentrations of EFV and NVP in HIV-infected individuals.
  
  
  METHODS
  Plasma drug concentrations were quantified by high-performance liquid chromatography in 143 HIV-infected individuals receiving either EFV or NVP. Genotyping for common alleles was performed by restriction fragment length polymorphism and Taqman assays. Individuals were genotyped for 11 single-nucleotide polymorphisms in 5 genes. CYP2B6 haplotypes were reconstructed by PHASE.
  
  
  RESULTS
  Plasma EFV concentrations were positively associated with CYP2B6 c.516G>T, c.785A>G, and c.983A>G single-nucleotide polymorphisms in HIV-infected individuals. Increased plasma concentrations of EFV and NVP were present in individuals with the CYP2B6*6/*6 or *6/*18 haplotype compared with CYP2B6*1/*1 [increase of 62% (95% confidence interval, 44.0-80.1) and 24% (95% confidence interval, 7.0-40.0), respectively, P < 0.01]. No significant association with other genes in relation to EFV or NVP concentrations was found.
  
  
  CONCLUSIONS
  In this study, a strong association of CYP2B6*6 and CYP2B6*18 alleles in relation to EFV and NVP plasma concentrations was found, which confirmed previous studies.
authors.affiliation: Department of Clinical Chemistry (AKC), Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands. s.heil@erasmusmc.nl
authors.forename: Sandra G
authors.initials: SG
authors.lastname: Heil
authors.forename: Marchina E
authors.initials: ME
authors.lastname: van der Ende
authors.forename: Paul W
authors.initials: PW
authors.lastname: Schenk
authors.forename: Ilse
authors.initials: I
authors.lastname: van der Heiden
authors.forename: Jan
authors.initials: J
authors.lastname: Lindemans
authors.forename: David
authors.initials: D
authors.lastname: Burger
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000480:Alkynes; D000483:Alleles; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D048588:Benzoxazines / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D003521:Cyclopropanes; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000493:pharmacokinetics*; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D019829:Nevirapine; D001189:Aryl Hydrocarbon Hydroxylases; C098320:efavirenz