title: Exploration of CYP450 and drug transporter genotypes and correlations with nevirapine exposure in Malawians.
abstract: OBJECTIVE
  Genetic polymorphisms have the potential to influence drug metabolism and vary among ethnic groups. This study evaluated the correlation of genetic polymorphisms with nevirapine pharmacokinetics exposure in Malawians.
  
  
  METHODS
  CYP450 2B6, 2D6, 3A4 and 3A5, ABCB1 and constitutive androstane receptor and pregnane X receptor, were analyzed for polymorphisms in 26 subjects.
  
  
  RESULTS
  Allele frequencies (variant) were: CYP2B6 514G>T (0.31) CYP2D6*4 (0.02); CYP2D6*17 (0.35); CYP3A4*1B (0.77); CYP3A5*3 (0.25); ABCB1 2677G>T (0.0), ABCB1 3435C>T (0.21), NR1I3 13711152T>C (0.02), NR1I2 44477T>C (0.10), NR1I2 63396C>T (0.33), NR1I2 6-bp indel (del: 0.17). CYP2B6 516G>T (non-wild-type/wild-type) correlated with nevirapine pharmacokinetic parameters; geometric mean ratios (95% CI): 1.75 (1.27-2.40) for area under the concentration time curve (AUC)(0-12 h), 1.58 (1.03-2.42) for C(0), and 0.53 (0.31-0.91) for clearance. In a multivariable model, nevirapine AUC increased by 1.5% per year of age (p < 0.0001), CYP2B6 516 T allele increased AUC by 92% (p < 0.0001), and CYP3A5*3 decreased AUC by 31% (p = 0.0027).
  
  
  CONCLUSIONS
  Allele frequencies were similar to other sub-Saharan African populations. The T allele for CYP2B6 516 was significantly associated with nevirapine exposure.
authors: University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, 3202 Kerr Hall, Chapel Hill, NC 27599-7569, USA.
authors: Kevin C
authors: KC
authors: Brown
authors: Mina C
authors: MC
authors: Hosseinipour
authors: Janelle M
authors: JM
authors: Hoskins
authors: Ranjit K
authors: RK
authors: Thirumaran
authors: Hsiao-Chuan
authors: HC
authors: Tien
authors: Ralf
authors: R
authors: Weigel
authors: Jean
authors: J
authors: Tauzie
authors: Ida
authors: I
authors: Shumba
authors: Jatinder K
authors: JK
authors: Lamba
authors: Erin G
authors: EG
authors: Schuetz
authors: Howard L
authors: HL
authors: McLeod
authors: Angela D M
authors: AD
authors: Kashuba
authors: Amanda H
authors: AH
authors: Corbett
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D017954:Africa South of the Sahara; D000483:Alleles; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D000090702:Constitutive Androstane Receptor; D021983:Cyclophilins / Q000235:genetics; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D005787:Gene Frequency / Q000235:genetics*; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics; D000097322:Peptidyl-Prolyl Isomerase D
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D001189:Aryl Hydrocarbon Hydroxylases; D000090702:Constitutive Androstane Receptor; D021983:Cyclophilins; D065702:Cytochrome P-450 CYP2B6; D019829:Nevirapine; D010089:Oxidoreductases, N-Demethylating; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; C513055:ABCB1 protein, human; C000625852:NR1I2 protein, human; C000716327:NR1I3 protein, human; C585599:CYP2B6 protein, human; C114456:PPID protein, human; D000097322:Peptidyl-Prolyl Isomerase D