title: Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients.
abstract: BACKGROUND
  Efavirenz (EFV) and nevirapine (NVP) are metabolized by cytochrome P450 2B6 (CYP2B6). Allele 516 G>T (Gln172His) is associated with diminished activity of this isoenzyme, and may lead to differences in drug exposure.
  
  
  METHODS
  We evaluated this allele as a pharmacogenetic marker of EFV and NVP pharmacokinetics and EFV toxicity in 167 participants receiving EFV and 59 receiving NVP recruited within the genetics project of the Swiss HIV Cohort Study. Drug concentrations were measured in plasma and in peripheral blood mononuclear cells (PBMCs) from the same sample. Neuropsychological toxicity of EFV (sleep disorders, mood disorders, fatigue) was assessed using a standardized questionnaire.
  
  
  CONCLUSIONS
  CYP2B6 516TT was associated with greater plasma and intracellular exposure to EFV, and greater plasma exposure to NVP. Intracellular drug concentration, and CYP2B6 genotype were predictors of EFV neuropsychological toxicity. CYP2B6 genotyping may be useful to complement an individualization strategy based on plasma drug determinations to increase the safety and tolerability of EFV.
authors.affiliation: Institute of Microbiology and Section of Infectious Diseases, University Hospital, Lausanne, Switzerland.
authors.forename: Margalida
authors.initials: M
authors.lastname: Rotger
authors.forename: Sara
authors.initials: S
authors.lastname: Colombo
authors.forename: Hansjakob
authors.initials: H
authors.lastname: Furrer
authors.forename: Gabriela
authors.initials: G
authors.lastname: Bleiber
authors.forename: Thierry
authors.initials: T
authors.lastname: Buclin
authors.forename: Belle L
authors.initials: BL
authors.lastname: Lee
authors.forename: Olivia
authors.initials: O
authors.lastname: Keiser
authors.forename: Jérôme
authors.initials: J
authors.lastname: Biollaz
authors.forename: Laurent
authors.initials: L
authors.lastname: Décosterd
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
mesh_terms: D000328:Adult; D000480:Alkynes; D000483:Alleles; D019380:Anti-HIV Agents / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D048588:Benzoxazines; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics*; D006679:HIV Seropositivity; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000494:pharmacology*; D016017:Odds Ratio; D010078:Oxazines / Q000494:pharmacology*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D020033:Protein Isoforms; D012044:Regression Analysis; D013997:Time Factors
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; D020033:Protein Isoforms; D019829:Nevirapine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz