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

Abstract

c 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 < 0.0001) with marked intersubject variability (e.g., the percent change in efavirenz AUC 0 -t ranged from 0.4% to ϳ224%). Voriconazole decreased efavirenz 8-hydroxylation by greater than 60% (P < 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 ‫؍‬ >0.8; P < 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.) H epatic cytochrome P450 (CYP) 2B6 (CYP2B6) was originally thought to play a minor role in human drug metabolism (1). Recent studies have revealed that hepatic CYP2B6 can account for 4 to 10% of the total hepatic CYP protein pool (2-4), as opposed to the Ͻ0.2% value reported in an earlier study (5). It is now considered to be the main enzyme responsible for the metabolism of many clinically important drugs and other compounds (1-4, 6, 7). Hepatic CYP2B6 protein expression and activity vary extensively (20-to 280-fold and 25-to 80-fold, respectively) among human liver tissues (3,4,8,9). Polymorphisms in the CYP2B6 gene and a host of nongenetic factors, including exposure to inducers and inhibitors (2-4, 10), contribute to the marked variability reported in enzyme activity. This variability accounts for the interpatient differences observed in the pharmacokinetics and effects of clinically important CYP2B6 substrates, including efavirenz (EFV) (10), methadone (11), ketamine (12), propofol (13), cyclophosphamide (14), bupropion (15), artemisinin derivatives (16), and nevirapine (17).Accurate assessment of hepatic CYP2B6 ac...

Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition

“…One of the greater unknowns is the reason why plasma R,R‐ and S,S‐hydroxybupropion concentrations are so different . Alternative CYP2B6 probes have also been suggested, such as 8‐hydroxylation of efavirenz, whose metabolism in vitro was considered to be a better predictor of clinical drug interactions than bupropion …”

Efavirenz Metabolism: Influence of Polymorphic CYP2B6 Variants and Stereochemistry

“…Cytochrome P450 2B6 (CYP2B6) is the major enzyme catalyzing S-8hydroxyefavirenz and thence 8,14-dihydroxyefavirenz formation, whereas CYP2A6 is responsible for 7-hydroxylation (Ward et al, 2003;Damle et al, 2008). CYP2B6 is a major determinant of clinical efavirenz metabolism and elimination; drug interactions resulting from CYP2B6 inhibition increase efavirenz exposure (Damle et al, 2008;Desta et al, 2016); and diminished CYP2B6 activity unmasks the influence of CYP2A6 on efavirenz exposure (di Iulio et al, 2009).…”

Variants in the CYP2B6 3′UTR Alter In Vitro and In Vivo CYP2B6 Activity: Potential Role of MicroRNAs

“…Data from 200 healthy non-pregnant female (n=83) and male (n=117) volunteers (18–55 years old) administered a single of efavirenz dose, a probe drug substrate of CYP2B6 activity, was obtained from the single dose phase of three previous studies, published and unpublished [19, 20]. These studies were approved by the Indiana University School of Medicine Institutional Review Board, conducted at the Indiana University School of Medicine Clinical Research Center and registered at http://www.clinicaltrials.gov (trial identifiers NCT00668395, NCT01104376, and NCT02401256).…”