title: Cytochrome P450 2B6 516G-->T is associated with plasma concentrations of nevirapine at both 200 mg twice daily and 400 mg once daily in an ethnically diverse population.
abstract: OBJECTIVE
  The aim of the study was to characterize the impact of the cytochrome P450 2B6 (CYP2B6), CYP3A4, CYP3A5 and ATP-binding cassette sub-family B member 1 (ABCB1) polymorphisms on nevirapine plasma concentrations.
  
  
  METHODS
  A total of 104 patients (82% male; 26% non-Caucasian) were genotyped for eight single nucleotide polymorphisms at four loci (CYP2B6, CYP3A4, CYP3A5 and MDR1). Nevirapine plasma concentrations were determined using high-performance liquid chromatography.
  
  
  RESULTS
  Non-Caucasian ethnicity [5609 ng/mL (n=27) for non-Caucasians vs. 3771 ng/mL (n=77) for Caucasians; P<0.0001] and CYP2B6 516G-->T [GG, 3574 ng/mL (n=50); GT, 4634 ng/mL (n=50); TT, 8170 ng/mL (n=4); P(analysis of variance (anova))=0.001] were significantly associated with a higher nevirapine trough concentration (C(trough)). The latter association was maintained with both 200 mg twice daily (bid) and 400 mg once daily (qd) dosing [GG, 3527 ng/mL (n=30); GT, 4525 ng/mL (n=32); TT, 7020 ng/mL (n=2); P(anova)=0.05 and GG, 3645 ng/mL (n=20); GT, 4861 ng/mL (n=17); TT, 9508 ng/mL (n=2); P(anova)=0.01, respectively]. In a multivariable analysis, CYP2B6 516G-->T and non-Caucasian ethnicity remained significant predictors of nevirapine C(trough) but CYP2B6 516G-->T homozygosity had the greatest effect (108% higher, 46% higher). No associations were found between nevirapine C(trough) and the remaining polymorphisms.
  
  
  CONCLUSIONS
  In this population, both non-Caucasian ethnicity and carriage of the variant allele of CYP2B6 516G-->T were significant predictors of nevirapine C(trough). The association between CYP2B6 516G-->T and higher plasma nevirapine exposure was maintained at both bid and qd dosing.
authors.affiliation: Department of HIV Medicine, Royal Free NHS Trust, London, UK. wambura@gmail.com
authors.forename: Tw
authors.initials: T
authors.lastname: Mahungu
authors.forename: Cj
authors.initials: C
authors.lastname: Smith
authors.forename: F
authors.initials: F
authors.lastname: Turner
authors.forename: D
authors.initials: D
authors.lastname: Egan
authors.forename: M
authors.initials: M
authors.lastname: Youle
authors.forename: Ma
authors.initials: M
authors.lastname: Johnson
authors.forename: S
authors.initials: S
authors.lastname: Khoo
authors.forename: Dj
authors.initials: Dj
authors.lastname: Back
authors.forename: A
authors.initials: A
authors.lastname: Owen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D000483:Alleles; D000704:Analysis of Variance; D044383:Black People / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000008:administration & dosage / Q000097:blood*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000097:blood*; D044465:White People / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018894:Reverse Transcriptase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D019829:Nevirapine; C585599:CYP2B6 protein, human; C510164:CYP3A5 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human