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Cytochrome P450 2B6 (CYP2B6) metabolizes clinically important drugs and other compounds. Its expression and activity vary widely among individuals, but quantitative estimation is hampered by the lack of safe and selective in vivo probes of CYP2B6 activity. Efavirenz, a nonnucleoside HIV-1 reverse transcriptase inhibitor, is mainly cleared by CYP2B6, an enzyme strongly inhibited in vitro by voriconazole. To test efavirenz metabolism as an in vivo probe of CYP2B6 activity, we quantified the inhibition of CYP2B6 activity by voriconazole in 61 healthy volunteers administered a single 100-mg oral dose of efavirenz with and without voriconazole administration. The kinetics of efavirenz metabolites demonstrated formation rate-limited elimination. Compared to control, voriconazole prolonged the elimination half-life (t 1/2 ) and increased both the maximum concentration of drug in serum (C max ) and the area under the concentration-time curve from 0 h to t (AUC 0-  t ) of efavirenz (mean change of 51%, 36%, and 89%, respectively) (P &lt; 0.0001) with marked intersubject variability (e.g., the percent change in efavirenz AUC 0-  t ranged from 0.4% to ∼224%). Voriconazole decreased efavirenz 8-hydroxylation by greater than 60% (P &lt; 0.0001), whereas its effect on 7-hydroxylation was marginal. The plasma concentration ratio of efavirenz to 8-hydroxyefavirenz, determined 1 to 6 h after dosing, was significantly increased by voriconazole and correlated with the efavirenz AUC 0-  t (Pearson r = &gt;0.8; P &lt; 0.0001). This study demonstrates the mechanisms of voriconazole-efavirenz interaction, establishes the use of a low dose of efavirenz as a safe and selective in vivo probe for phenotyping CYP2B6 activity, and identifies several easy-to-use indices that should enhance understanding of the mechanisms of CYP2B6 interindividual variability. (This study is registered at ClinicalTrials.gov under identifier NCT01104376.).

Inhibition of Cytochrome P450 2B6 Activity by Voriconazole Profiled Using Efavirenz Disposition in Healthy Volunteers