Mechanism of Ritonavir Changes in Methadone Pharmacokinetics and Pharmacodynamics: I. Evidence Against CYP3A Mediation of Methadone Clearance

Abstract

Ritonavir diminishes methadone plasma concentrations, attributed to CYP3A induction, but actual mechanisms are unknown. We determined ritonavir effects on stereoselective methadone pharmacokinetics and clinical effects (pupillary miosis) in healthy HIV-negative volunteers. Subjects received intravenous plus oral (deuterium-labeled) racemic methadone after nothing, short-term (3 day) 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 methadone hepatic N-demethylation 50-80%, extraction 2-fold, and clearance 2-fold. 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.

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

“…Previous clinical studies also showed methadone bioavailability apparently unrelated to P-gp (or fexofenadine transporter) activity. Specifically, ritonavir, indinavir, ritonavir-indinavir, nelfinavir, and efavirenz, respectively, inhibited, inhibited, inhibited, induced, and induced fexofenadine efflux (suggesting altered P-gp activity), whereas methadone bioavailability was unchanged, unchanged, unchanged, decreased, and unchanged (Kharasch et al, 2008a(Kharasch et al, , 2009a(Kharasch et al, , b, 2012a. Together, these results do not suggest that intestinal P-gp significantly mediates methadone absorption and first-pass extraction, and thus transporter mechanisms of methadone bioavailability and drug interactions remain unclear.…”

“…and oral methadone (Kharasch et al, 2004a(Kharasch et al, , 2008a(Kharasch et al, , 2009a(Kharasch et al, ,b, 2012a. Subjects received i.v.…”

“…Pharmacokinetic data were analyzed using noncompartmental methods (Phoenix, Pharsight Corp, Mountain View, CA), assuming complete absorption, as described previously (Kharasch et al, 2004a(Kharasch et al, ,b, 2007(Kharasch et al, , 2008a(Kharasch et al, ,b, 2009a(Kharasch et al, ,b, 2012a. AUC was determined using the trapezoidal rule.…”

“…A comprehensive crossover investigation in healthy volunteers evaluated the metabolism and clearance of both intravenous and oral methadone. Clearances of intravenous and oral alfentanil, a nonselective CYP3A4/5 (henceforth referred to as CYP3A) substrate, phenotyped hepatic and first-pass CYP3A activities and oral fexofenadine probed P-gp (Kharasch et al, 2004b(Kharasch et al, , 2005(Kharasch et al, , 2008a(Kharasch et al, ,b, 2009a(Kharasch et al, ,b, 2011a(Kharasch et al, ,b, 2012a.…”

Contemporary Clinical Opioid Use: Opportunities and Challenges

“…In part, mishaps with methadone are a striking example that practitioners' basic understanding of opioid pharmacology is simply failing to keep up with the clinical applications of these drugs, a problem compounded by systematic deficiencies in overall knowledge acquisition and dissemination. 5,26 The most convincing metric of this failure is the mounting number of patient deaths. As identified by the Substance Abuse and Mental Health Services Administration, "Half of methadone deaths are pain patients who are being mismanaged by physicians who lack sufficient knowledge or skills to use methadone in the treatment of pain."…”