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

• Published in: Drug metabolism and pharmacokinetics Vol. 31; no. 2; pp. 107 - 116
• Main 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
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2016
• Subjects: 8-Hydroxylation; Adolescent; Adult; Anti-Retroviral Agents - blood; Anti-Retroviral Agents - metabolism; Anti-Retroviral Agents - pharmacokinetics; Benzoxazines - blood; Benzoxazines - metabolism; Benzoxazines - pharmacokinetics; Cross-Over Studies; CYP2B6; Cytochrome P-450 CYP2B6 - metabolism; Cytochrome P-450 CYP2B6 Inducers - pharmacology; Efavirenz; Female; Healthy Volunteers; Humans; Hydroxylation - drug effects; Induction; In vivo probe; Male; Middle Aged; Rifampin; Rifampin - pharmacology; Young Adult; In vivo probe; CYP2B6; Induction; Rifampin; Efavirenz; 8-Hydroxylation
• ISSN: 1347-4367; 1880-0920; 1880-0920
• DOI: 10.1016/j.dmpk.2015.07.002

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 (Cmax) 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 Cmax 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. [Display omitted]