title: Effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites: exploration of a novel CYP2B6 phenotyping index.
abstract: OBJECTIVE
  To evaluate the effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites in relation to the CYP2B6*6 genotype and explore potential phenotyping indices for CYP2B6 activity in vivo using a low dose of oral efavirenz.
  
  
  METHODS
  We conducted a randomized three phase crossover study in 17 healthy Korean subjects pre-genotyped for the CYP2B6*6 allele (CYP2B6*1/*1, n = 6; *1/*6, n = 6; *6/*6, n = 5). Subjects were pretreated with clopidogrel (75 mg day(-1) for 4 days), itraconazole (200 mg day(-1) for 6 days), or placebo and then given a single dose of efavirenz (200 mg). The plasma (0-120 h) and urine (0-24 h) concentrations of efavirenz and its metabolites (7- and 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz) were determined by LC/MS/MS.
  
  
  RESULTS
  This study is the first to delineate quantitatively the full (phase I and II) metabolic profile of efavirenz and its three hydroxyl metabolites in humans. Clopidogrel pretreatment markedly decreased AUC(0,48 h), C(max) and Ae(0,24 h) for 8,14-dihydroxyefavirenz, compared with placebo; 95% CI of the ratios were 0.55, 0.73, 0.30, 0.45 and 0.25, 0.47, respectively. The 8,14-dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio was significantly correlated with the weight-adjusted CL/F of efavirenz (r(2) ≈ 0.4, P < 0.05), differed with CYP2B6*6 genotype and was affected by clopidogrel pretreatment (P < 0.05) but not by itraconazole pretreatment.
  
  
  CONCLUSIONS
  The disposition of 8,14-dihydroxy-EFV appears to be sensitive to CYP2B6 activity alterations in human subjects. The 8,14-dihydroxyefaviremz : efavirenz AUC(0,120 h) ratio is attractive as a candidate phenotyping index for CYP2B6 activity in vivo.
authors.affiliation: Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, South Korea.
authors.forename: Fen
authors.initials: F
authors.lastname: Jiang
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Shon
authors.forename: Chang-Woo
authors.initials: CW
authors.lastname: Yeo
authors.forename: Ho-Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Kwang-Hyeon
authors.initials: KH
authors.lastname: Liu
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Bae
authors.forename: Sang-Seop
authors.initials: SS
authors.lastname: Lee
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D048588:Benzoxazines / Q000493:pharmacokinetics*; D000077144:Clopidogrel; D018592:Cross-Over Studies; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D017964:Itraconazole / Q000494:pharmacology*; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D010641:Phenotype; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000935:Antifungal Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D010975:Platelet Aggregation Inhibitors; D017964:Itraconazole; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz; D013988:Ticlopidine