Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers. Issue 2 (April 2016)

• Record Type: Journal Article
• Authors: Cho, Doo-Yeoun; Shen, Joan H.Q.; Lemler, Suzanne M.; Skaar, Todd C.; Li, Lang; Blievernicht, Julia; Zanger, Ulrich M.; Kim, Kwon-Bok; Shin, Jae-Gook; Flockhart, David A.; Desta, Zeruesenay
• Is Part Of: Drug metabolism and pharmacokinetics. Volume 31:Issue 2(2016)
• Page Start: 107
• Page End: 116
• Publication Date: 2016-04
• Subjects: Rifampin -- Efavirenz -- 8-Hydroxylation -- CYP2B6 -- Induction -- In vivo probe; Drugs -- Metabolism -- Periodicals; Pharmacokinetics -- Periodicals; 615.7
• DOI: 10.1016/j.dmpk.2015.07.002
• Languages: English
• ISSNs: 1347-4367

Abstract

Abstract: The effect of rifampin on the in vivo metabolism of the antiretroviral drug efavirenz was evaluated in healthy volunteers. In a cross-over placebo control trial, healthy subjects ( n = 20) were administered a single 600 mg oral dose of efavirenz after pretreatment with placebo or rifampin (600 mg/day for 10 days). Plasma and urine concentrations of efavirenz, 8-hydroxyefavirenz and 8, 14-dihydroxyefavirenz were measured by LC–MS/MS. Compared to placebo treatment, rifampin increased the oral clearance (by ∼2.5-fold) and decreased maximum plasma concentration ( C max ) and area under the plasma concentration–time curve (AUC0–∞ ) of efavirenz (by ∼1.6- and ∼2.5-fold respectively) ( p < 0.001). Rifampin treatment substantially increased the C max and AUC0–12h of 8-hydroxyefavirenz and 8, 14-dihydroxyefavirenz, metabolic ratio (AUC0–72h of metabolites to AUC0–72h efavirenz) and the amount of metabolites excreted in urine (Ae0–12hr ) (all, p < 0.01). Female subjects had longer elimination half-life (1.6–2.2-fold) and larger weight-adjusted distribution volume (1.6–1.9-fold) of efavirenz than male subjects ( p < 0.05) in placebo and rifampin treated groups respectively. In conclusion, rifampin enhances CYP2B6-mediated efavirenz 8-hydroxylation in vivo . The metabolism of a single oral dose of efavirenz may be a suitable in vivo marker of CYP2B6 activity to evaluate induction drug interactions involving this enzyme. Graphical abstract: