title: Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers.
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 (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.
authors.affiliation: Indiana University School of Medicine, Department of Medicine, Division of Clinical Pharmacology, Indianapolis, IN 46202, USA.
authors.forename: Doo-Yeoun
authors.initials: DY
authors.lastname: Cho
authors.affiliation: Indiana University School of Medicine, Department of Medicine, Division of Clinical Pharmacology, Indianapolis, IN 46202, USA.
authors.forename: Joan H Q
authors.initials: JH
authors.lastname: Shen
authors.affiliation: Indiana University School of Medicine, Department of Medicine, Division of Clinical Pharmacology, Indianapolis, IN 46202, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Lemler
authors.affiliation: Indiana University School of Medicine, Department of Medicine, Division of Clinical Pharmacology, Indianapolis, IN 46202, USA.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Skaar
authors.affiliation: Indiana University School of Medicine, Department of Medicine, Division of Clinical Pharmacology, Indianapolis, IN 46202, USA.
authors.forename: Lang
authors.initials: L
authors.lastname: Li
authors.affiliation: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Blievernicht
authors.affiliation: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
authors.affiliation: Inje University College of Medicine, Inje University Busan Paik Hospital, Busan 614-735, Republic of Korea.
authors.forename: Kwon-Bok
authors.initials: KB
authors.lastname: Kim
authors.affiliation: Inje University College of Medicine, Inje University Busan Paik Hospital, Busan 614-735, Republic of Korea.
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.affiliation: Indiana University School of Medicine, Department of Medicine, Division of Clinical Pharmacology, Indianapolis, IN 46202, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.affiliation: Indiana University School of Medicine, Department of Medicine, Division of Clinical Pharmacology, Indianapolis, IN 46202, USA. Electronic address: zdesta@iu.edu.
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
mesh_terms: D000293:Adolescent; D000328:Adult; D044966:Anti-Retroviral Agents / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D048588:Benzoxazines / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D065702:Cytochrome P-450 CYP2B6 / Q000378:metabolism*; D065695:Cytochrome P-450 CYP2B6 Inducers / Q000494:pharmacology*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D012293:Rifampin / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D044966:Anti-Retroviral Agents; D048588:Benzoxazines; D065695:Cytochrome P-450 CYP2B6 Inducers; D065702:Cytochrome P-450 CYP2B6; C570209:8-hydroxyefavirenz; D012293:Rifampin
keywords: 8-Hydroxylation; CYP2B6; Efavirenz; Induction; In vivo probe; Rifampin