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Mechanism of Ritonavir Changes in Methadone Pharmacokinetics and Pharmacodynamics: I. Evidence Against CYP3A Mediation of Methadone Clearance
Author(s) -
Kharasch ED,
Bedynek PS,
Park S,
Whittington D,
Walker A,
Hoffer C
Publication year - 2008
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2008.104
Subject(s) - ritonavir , methadone , pharmacokinetics , cyp3a , pharmacology , chemistry , medicine , metabolism , immunology , cytochrome p450 , human immunodeficiency virus (hiv) , viral load , antiretroviral therapy
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. Clinical Pharmacology & Therapeutics (2008); 84 , 4, 497–505 doi: 10.1038/clpt.2008.104