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

Doo Yeoun Cho, Joan H Q Shen, Suzanne M. Lemler, Todd Skaar, Lang Li, Julia Blievernicht, Ulrich M. Zanger, Kwon Bok Kim, Jae Gook Shin, David A. Flockhart, Zeruesenay Desta

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)107-116
Number of pages10
JournalDrug Metabolism and Pharmacokinetics
Volume31
Issue number2
DOIs
StatePublished - Apr 1 2016

Fingerprint

efavirenz
Hydroxylation
Rifampin
Healthy Volunteers
Placebos
Urine
Cytochrome P-450 CYP2B6
Drug Interactions

Keywords

  • 8-Hydroxylation
  • CYP2B6
  • Efavirenz
  • In vivo probe
  • Induction
  • Rifampin

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Pharmaceutical Science

Cite this

Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers. / Cho, Doo Yeoun; Shen, Joan H Q; Lemler, Suzanne M.; Skaar, Todd; Li, Lang; Blievernicht, Julia; Zanger, Ulrich M.; Kim, Kwon Bok; Shin, Jae Gook; Flockhart, David A.; Desta, Zeruesenay.

In: Drug Metabolism and Pharmacokinetics, Vol. 31, No. 2, 01.04.2016, p. 107-116.

Research output: Contribution to journalArticle

Cho, DY, Shen, JHQ, Lemler, SM, Skaar, T, Li, L, Blievernicht, J, Zanger, UM, Kim, KB, Shin, JG, Flockhart, DA & Desta, Z 2016, 'Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers', Drug Metabolism and Pharmacokinetics, vol. 31, no. 2, pp. 107-116. https://doi.org/10.1016/j.dmpk.2015.07.002
Cho, Doo Yeoun ; Shen, Joan H Q ; Lemler, Suzanne M. ; Skaar, Todd ; Li, Lang ; Blievernicht, Julia ; Zanger, Ulrich M. ; Kim, Kwon Bok ; Shin, Jae Gook ; Flockhart, David A. ; Desta, Zeruesenay. / Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers. In: Drug Metabolism and Pharmacokinetics. 2016 ; Vol. 31, No. 2. pp. 107-116.
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