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Mechanism of efavirenz influence on methadone pharmacokinetics and pharmacodynamics.

Publication ,  Journal Article
Kharasch, ED; Whittington, D; Ensign, D; Hoffer, C; Bedynek, PS; Campbell, S; Stubbert, K; Crafford, A; London, A; Kim, T
Published in: Clin Pharmacol Ther
April 2012

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.

Duke Scholars

Published In

Clin Pharmacol Ther

DOI

EISSN

1532-6535

Publication Date

April 2012

Volume

91

Issue

4

Start / End Page

673 / 684

Location

United States

Related Subject Headings

  • Young Adult
  • Pharmacology & Pharmacy
  • Oxidoreductases, N-Demethylating
  • Methadone
  • Male
  • Humans
  • Hepatocytes
  • Female
  • Drug Interactions
  • Cytochrome P-450 CYP3A
 

Citation

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Kharasch, E. D., Whittington, D., Ensign, D., Hoffer, C., Bedynek, P. S., Campbell, S., … Kim, T. (2012). Mechanism of efavirenz influence on methadone pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther, 91(4), 673–684. https://doi.org/10.1038/clpt.2011.276
Kharasch, E. D., D. Whittington, D. Ensign, C. Hoffer, P. S. Bedynek, S. Campbell, K. Stubbert, A. Crafford, A. London, and T. Kim. “Mechanism of efavirenz influence on methadone pharmacokinetics and pharmacodynamics.Clin Pharmacol Ther 91, no. 4 (April 2012): 673–84. https://doi.org/10.1038/clpt.2011.276.
Kharasch ED, Whittington D, Ensign D, Hoffer C, Bedynek PS, Campbell S, et al. Mechanism of efavirenz influence on methadone pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2012 Apr;91(4):673–84.
Kharasch, E. D., et al. “Mechanism of efavirenz influence on methadone pharmacokinetics and pharmacodynamics.Clin Pharmacol Ther, vol. 91, no. 4, Apr. 2012, pp. 673–84. Pubmed, doi:10.1038/clpt.2011.276.
Kharasch ED, Whittington D, Ensign D, Hoffer C, Bedynek PS, Campbell S, Stubbert K, Crafford A, London A, Kim T. Mechanism of efavirenz influence on methadone pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2012 Apr;91(4):673–684.
Journal cover image

Published In

Clin Pharmacol Ther

DOI

EISSN

1532-6535

Publication Date

April 2012

Volume

91

Issue

4

Start / End Page

673 / 684

Location

United States

Related Subject Headings

  • Young Adult
  • Pharmacology & Pharmacy
  • Oxidoreductases, N-Demethylating
  • Methadone
  • Male
  • Humans
  • Hepatocytes
  • Female
  • Drug Interactions
  • Cytochrome P-450 CYP3A