| Lack of Indinavir Effects on Methadone Disposition Despite Inhibition of Hepatic and Intestinal Cytochrome P4503A (CYP3A). | |
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MedLine Citation:
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PMID: 22273859 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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BACKGROUND: : Methadone disposition and pharmacodynamics are highly susceptible to interactions with antiretroviral drugs. Methadone clearance and drug interactions have been attributed to cytochrome P4503A4 (CYP3A4), but actual mechanisms are unknown. Drug interactions can be clinically and mechanistically informative. This investigation assessed effects of the protease inhibitor indinavir on methadone pharmacokinetics and pharmacodynamics, hepatic and intestinal CYP3A4/5 activity (using alfentanil), and intestinal transporter activity (using fexofenadine). METHODS: : Twelve healthy volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone. This was repeated after 2 weeks of indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by miosis. RESULTS: : Indinavir significantly inhibited hepatic and first-pass CYP3A activity. Intravenous alfentanil systemic clearance and hepatic extraction were reduced to 40-50% of control, apparent oral clearance to 30% of control, and intestinal extraction decreased by half, indicating 50% and 70% inhibition of hepatic and first-pass CYP3A activity. Indinavir increased fexofenadine area under the plasma concentration-time curve 3-fold, suggesting significant P-glycoprotein inhibition. Indinavir had no significant effects on methadone plasma concentrations, methadone N-demethylation, systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Methadone plasma concentration-effect relationships were unaffected by indinavir. CONCLUSIONS: : Despite significant inhibition of hepatic and intestinal CYP3A activity, indinavir had no effect on methadone N-demethylation and clearance, suggesting little or no role for CYP3A in clinical disposition of single-dose methadone. Inhibition of gastrointestinal transporter activity had no influence of methadone bioavailability. |
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Authors:
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Evan D Kharasch; Pamela Sheffels Bedynek; Christine Hoffer; Alysa Walker; Dale Whittington |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Anesthesiology Volume: 116 ISSN: 1528-1175 ISO Abbreviation: Anesthesiology Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-01-25 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 1300217 Medline TA: Anesthesiology Country: United States |
Other Details:
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Languages: eng Pagination: 432-47 Citation Subset: AIM; IM |
Affiliation:
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* Russell D. and Mary B. Shelden Professor of Anesthesiology, Director, Division of Clinical and Translational Research, Department of Anesthesiology, Professor of Biochemistry and Molecular Biophysics, Vice Chancellor for Research, Washington University in St. Louis, St. Louis, Missouri. † Research Scientist, ‡ Research Study Coordinator, Department of Anesthesiology, University of Washington, Seattle, Washington. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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