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Research ArticleArticle

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Evan D. Kharasch and Kristi Stubbert
Drug Metabolism and Disposition December 2013, 41 (12) 2166-2174; DOI: https://doi.org/10.1124/dmd.113.053991
Evan D. Kharasch
Department of Anesthesiology, Division of Clinical and Translational Research (E.D.K., K.S.), and Department of Biochemistry and Molecular Biophysics (E.D.K.), Washington University in St. Louis, St. Louis, Missouri
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Kristi Stubbert
Department of Anesthesiology, Division of Clinical and Translational Research (E.D.K., K.S.), and Department of Biochemistry and Molecular Biophysics (E.D.K.), Washington University in St. Louis, St. Louis, Missouri
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Abstract

Plasma concentrations of orally administered methadone are reduced by the human immunodeficiency virus protease inhibitor combination ritonavir and lopinavir, but the mechanism is unknown. Methadone metabolism, clearance, and drug interactions have been attributed to CYP3A4, but this remains controversial. This investigation assessed the effects of acute (2 days) and steady-state (2 weeks) ritonavir-lopinavir on intravenous and oral methadone metabolism and clearance, hepatic and intestinal CYP3A4/5 activity (using the probe substrate intravenous and oral alfentanil), and intestinal transporter activity (using oral fexofenadine) in healthy volunteers. Plasma and urine concentrations of methadone and metabolite enantiomers, and other analytes, were determined by mass spectrometry. Acute and chronic ritonavir-lopinavir reduced plasma methadone enantiomer concentrations in half, with an average 2.6- and 1.5-fold induction of systemic and apparent oral methadone clearances. Induction was attributable to stereoselectively increased hepatic methadone N-demethylation, hepatic extraction, and hepatic clearance, and there was a strong correlation between methadone N-demethylation and clearance. Methadone renal clearance was unchanged. Alfentanil’s systemic clearance and hepatic extraction, apparent oral clearance, and intestinal extraction were reduced to 25%, 16%, and 35% of control, indicating strong inhibition of hepatic and intestinal CYP3A activities. Ritonavir-lopinavir (acute > chronic) increased fexofenadine exposure, suggesting intestinal P-glycoprotein inhibition. No correlation was found between methadone clearance and CYP3A activity. Acute and steady-state ritonavir-lopinavir stereoselectively induced methadone N-demethylation and clearance, despite significant inhibition of hepatic and intestinal CYP3A activity. Ritonavir-lopinavir inhibited intestinal transporters activity but had no effect on methadone bioavailability. These results do not support a significant role for CYP3A or ritonavir-lopinavir-inhibitable intestinal transporters in single-dose methadone disposition.

Footnotes

    • Received July 31, 2013.
    • Accepted September 25, 2013.
  • This work was supported by the National Institutes of Health [Grants R01-GM63674, R01-DA14211, K24-DA0041, and UL1-TR000448].

  • dx.doi.org/10.1124/dmd.113.053991.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (12)
Drug Metabolism and Disposition
Vol. 41, Issue 12
1 Dec 2013
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Research ArticleArticle

Methadone Interaction with Ritonavir-Lopinavir

Evan D. Kharasch and Kristi Stubbert
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2166-2174; DOI: https://doi.org/10.1124/dmd.113.053991

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Research ArticleArticle

Methadone Interaction with Ritonavir-Lopinavir

Evan D. Kharasch and Kristi Stubbert
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2166-2174; DOI: https://doi.org/10.1124/dmd.113.053991
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