Skip to main content
Journal cover image

Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: I. Evidence against CYP3A mediation of methadone clearance.

Publication ,  Journal Article
Kharasch, ED; Bedynek, PS; Park, S; Whittington, D; Walker, A; Hoffer, C
Published in: Clin Pharmacol Ther
October 2008

Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. We determined ritonavir effects on stereoselective methadone pharmacokinetics and clinical effects (pupillary miosis) in healthy human immunodeficiency virus-negative volunteers. Subjects received intravenous plus oral (deuterium-labeled) racemic methadone after no ritonavir, short-term (3-day) ritonavir, and steady-state ritonavir. Acute and steady-state ritonavir, respectively, caused 1.5- and 2-fold induction of systemic and apparent oral R- and S-methadone clearances. Ritonavir increased renal clearance 40-50%, and stereoselectively (S > R) increased hepatic methadone N-demethylation 50-80%, extraction twofold, and clearance twofold. Bioavailability was unchanged despite significant inhibition of intestinal P-glycoprotein. Intestinal and hepatic CYP3A was inhibited > 70%. Ritonavir shifted methadone plasma concentration-miosis curves leftward and upward. Rapid ritonavir induction of methadone clearance results from increased renal clearance and induced hepatic metabolism. Induction of methadone metabolism occurred despite profound CYP3A inhibition, suggesting no role for CYP3A in clinical methadone metabolism and clearance. Ritonavir may alter methadone pharmacodynamics.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Clin Pharmacol Ther

DOI

ISSN

0009-9236

Publication Date

October 2008

Volume

84

Issue

4

Start / End Page

497 / 505

Location

United States

Related Subject Headings

  • Stereoisomerism
  • Ritonavir
  • Pupil
  • Pharmacology & Pharmacy
  • Narcotics
  • Methadone
  • Male
  • Humans
  • HIV Protease Inhibitors
  • Female
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Kharasch, E. D., Bedynek, P. S., Park, S., Whittington, D., Walker, A., & Hoffer, C. (2008). Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: I. Evidence against CYP3A mediation of methadone clearance. Clin Pharmacol Ther, 84(4), 497–505. https://doi.org/10.1038/clpt.2008.104
Kharasch, E. D., P. S. Bedynek, S. Park, D. Whittington, A. Walker, and C. Hoffer. “Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: I. Evidence against CYP3A mediation of methadone clearance.Clin Pharmacol Ther 84, no. 4 (October 2008): 497–505. https://doi.org/10.1038/clpt.2008.104.
Kharasch ED, Bedynek PS, Park S, Whittington D, Walker A, Hoffer C. Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: I. Evidence against CYP3A mediation of methadone clearance. Clin Pharmacol Ther. 2008 Oct;84(4):497–505.
Kharasch, E. D., et al. “Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: I. Evidence against CYP3A mediation of methadone clearance.Clin Pharmacol Ther, vol. 84, no. 4, Oct. 2008, pp. 497–505. Pubmed, doi:10.1038/clpt.2008.104.
Kharasch ED, Bedynek PS, Park S, Whittington D, Walker A, Hoffer C. Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: I. Evidence against CYP3A mediation of methadone clearance. Clin Pharmacol Ther. 2008 Oct;84(4):497–505.
Journal cover image

Published In

Clin Pharmacol Ther

DOI

ISSN

0009-9236

Publication Date

October 2008

Volume

84

Issue

4

Start / End Page

497 / 505

Location

United States

Related Subject Headings

  • Stereoisomerism
  • Ritonavir
  • Pupil
  • Pharmacology & Pharmacy
  • Narcotics
  • Methadone
  • Male
  • Humans
  • HIV Protease Inhibitors
  • Female