Efavirenz diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but actual mechanisms are unknown. This investigation determined the effects of two weeks of efavirenz (600 mg daily) on hepatic and intestinal CYP3A4/5 (probed with intravenous and oral alfentanil), hepatic CYP2B6 (oral efavirenz hydroxylation) and intestinal transporter (oral fexofenadine) activities, and on methadone pharmacokinetics and pharmacodynamics in healthy volunteers. It also assessed efavirenz effects on CYP expression and activity in human hepatocytes. Efavirenz significantly induced systemic and oral alfentanil clearance 2- to 5-fold, increased alfentanil hepatic and intestinal extraction ratios, and significantly induced apparent 8-hydroxyefavirenz formation clearance. Efavirenz also moderately decreased fexofenadine plasma concentrations, suggesting decreased intestinal uptake and/or increased P-glycoprotein-mediated efflux. Efavirenz induced CYP2B6 and CYP3A4 expression, activity, and methadone metabolism in human hepatocytes. Efavirenz coinduces hepatic CYP2B6 and CYP3A4/5 activities, coinduces hepatic and intestinal CYP3A4/5, and coinduces gastrointestinal CYP3A and xenobiotic efflux transporters.

Methadone N-demethylation in vitro is catalyzed by hepatic cytochrome P4502B6 (CYP2B6) and CYP3A4, but clinical disposition is often attributed to CYP3A4. This investigation tested the hypothesis that CYP2B6 is a prominent CYP isoform responsible for clinical methadone N-demethylation and clearance, using the in vivo mechanism-based CYP2B6 inhibitor ticlopidine, given orally for 4 days. A preliminary clinical investigation with the CYP3A4/5 substrate probe alfentanil established that ticlopidine did not inhibit intestinal or hepatic CYP3A4/5. Subjects received intravenous plus oral (deuterium-labeled) racemic methadone before and after ticlopidine. Ticlopidine significantly and stereoselectively (S>R) inhibited methadone N-demethylation, decreasing plasma metabolite/methadone area under the curve ratios and metabolite formation clearances. Ticlopidine also significantly increased the dose-adjusted plasma area under the curve for R- and S-methadone by 20% and 60%, respectively, after both intravenous and oral dosing. CYP2B6 inhibition reduces methadone N-demethylation and clearance, and alters methadone concentrations, demonstrating a predominant role for CYP2B6 in clinical methadone disposition.

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) ritonavirlopinavir 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.

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