Effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites: exploration of a novel CYP2B6 phenotyping index

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To evaluate the effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites in relation to theCYP2B6*6genotype and explore potential phenotyping indices for CYP2B6 activityin vivousing a low dose of oral efavirenz.


We conducted a randomized three phase crossover study in 17 healthy Korean subjects pre-genotyped for theCYP2B6*6allele (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.


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),Cmax 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/Fof efavirenz (r2≈ 0.4,P< 0.05), differed withCYP2B6*6genotype and was affected by clopidogrel pretreatment (P< 0.05) but not by itraconazole pretreatment.


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 activityin vivo.

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