Mechanism of efavirenz influence on methadone pharmacokinetics and pharmacodynamics

Clin Pharmacol Ther. 2012 Apr;91(4):673-84. doi: 10.1038/clpt.2011.276. Epub 2012 Mar 7.


Mechanisms by which efavirenz diminishes methadone plasma concentrations are unknown. This investigation determined efavirenz influence on clinical methadone disposition and miosis, intravenous and oral alfentanil clearance (hepatic and intestinal cytochrome P450 3A4/5 (CYP3A4/5) activity), fexofenadine disposition (intestinal transporters activity), and efavirenz clearance and 8-hydroxylation (CYP2B6 activity), and human hepatocyte effects. Efavirenz induced systemic and oral alfentanil clearances two- to fivefold and induced efavirenz 8-hydroxylation. Efavirenz stereoselectively decreased methadone plasma concentrations 50-70%. Methadone systemic and oral clearances, hepatic clearance and extraction ratio, N-demethylation, and metabolite formation clearance were stereoselectively increased two- to threefold. Bioavailability decreased. Efavirenz shifted methadone concentration-miosis curves leftward and upward. Efavirenz induced hepatocyte CYP2B6 and CYP3A4 expression, activity, and methadone N-demethylation. Results show that efavirenz coinduced hepatic CYP2B6 and CYP3A4/5, coinduced hepatic and intestinal CYP3A4/5, and coinduced gastrointestinal CYP3A4/5 and efflux transporters. Methadone disposition was most consistent with efavirenz induction of hepatic CYP2B6-mediated methadone N-demethylation. Efavirenz may alter methadone pharmacodynamics.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Alkynes
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Benzoxazines / blood*
  • Benzoxazines / pharmacokinetics*
  • Benzoxazines / pharmacology
  • Cross-Over Studies
  • Cyclopropanes
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A / metabolism
  • Drug Interactions / physiology
  • Female
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Humans
  • Male
  • Methadone / blood*
  • Methadone / pharmacokinetics*
  • Methadone / pharmacology
  • Oxidoreductases, N-Demethylating / metabolism
  • Young Adult


  • Alkynes
  • Benzoxazines
  • Cyclopropanes
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Oxidoreductases, N-Demethylating
  • efavirenz
  • Methadone