title: Associations between CYP2B6 polymorphisms and pharmacokinetics after a single dose of nevirapine or efavirenz in African americans.
abstract: BACKGROUND
  Polymorphisms in CYP2B6 affect the steady-state plasma concentrations of nevirapine and efavirenz. In many resource-limited countries, a single dose of nevirapine has been widely prescribed to pregnant women at delivery, to reduce mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1). We characterized associations between genetic polymorphisms and the pharmacokinetics of single doses of nevirapine and efavirenz.
  
  
  METHODS
  Plasma drug concentrations were determined over the 13-day period after administration of a 200-mg oral dose of nevirapine to nonpregnant, HIV-negative African Americans. A 600-mg oral dose of efavirenz was subsequently administered, and pharmacokinetic sampling was repeated. Pharmacokinetic parameters were estimated using a noncompartmental approach. Primary analyses involved 2 CYP2B6 polymorphisms (516G --> T and 983T --> C) known to predict increased steady-state plasma nevirapine and efavirenz exposure. Exploratory analyses involved another 51 polymorphisms in CYP2B6, ABCB1, CYP3A4, and CYP3A5.
  
  
  RESULTS
  On the basis of the composite CYP2B6 516/983 genotype, the 34 participants comprised 10 extensive, 17 intermediate, and 7 slow metabolizer genotypes. The composite CYP2B6 516/983 genotype was significantly associated with plasma drug exposure and clearance for efavirenz but not nevirapine. Exploratory analyses suggested possible associations between additional CYP2B6 polymorphisms and the pharmacokinetics of nevirapine and efavirenz.
  
  
  CONCLUSIONS
  Selective pressure for drug-resistant HIV-1 after administration of single-dose nevirapine may not differ substantially according to CYP2B6 516/983 genotype. Additional polymorphisms, genes, and populations warrant further study.
authors.affiliation: USA. david.w.haas@vanderbilt.edu
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
authors.forename: Tebeb
authors.initials: T
authors.lastname: Gebretsadik
authors.forename: Gail
authors.initials: G
authors.lastname: Mayo
authors.forename: Usha N
authors.initials: UN
authors.lastname: Menon
authors.forename: Edward P
authors.initials: EP
authors.lastname: Acosta
authors.forename: Ayumi
authors.initials: A
authors.lastname: Shintani
authors.forename: Michael
authors.initials: M
authors.lastname: Floyd
authors.forename: C Michael
authors.initials: CM
authors.lastname: Stein
authors.forename: Grant R
authors.initials: GR
authors.lastname: Wilkinson
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D044383:Black People / Q000235:genetics*; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D005838:Genotype; D018023:HIV Seronegativity; D006801:Humans; D015810:Linkage Disequilibrium; D008657:Metabolic Clearance Rate; D019829:Nevirapine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D012449:Safety; D001741:Black or African American
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D019829:Nevirapine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz