Ritonavir diminishes methadone plasma concentrations, attributed to CYP3A, but mechanisms are unknown. We determined short-term (2 day) and steady-state (2 week) ritonavir effects on intestinal/hepatic CYP3A (probed with IV and oral alfentanil, and miosis), P-glycoprotein (fexofenadine) and methadone pharmacokinetics and pharmacodynamics in healthy volunteers. Acute ritonavir increased the AUC0-∞/dose ratio (ritonavir/control) for oral alfentanil 25-fold. Steady-state ritonavir increased the AUC0-∞/dose ratio for intravenous and oral alfentanil 4- and 10-fold, respectively, reduced hepatic extraction (0.26 to 0.07), intestinal extraction (0.51 to zero), and increased bioavailability (37 to 95%). Acute ritonavir inhibits first-pass CYP3A >96%. Chronic ritonavir inhibits hepatic (>70%) and first-pass (>90%) CYP3A. Acute and steady-state ritonavir increased fexofenadine AUC0-∞ 2.8- and 1.4-fold, suggesting P-glycoprotein inhibition. Steady-state ritonavir caused mild apparent induction of P-glycoprotein and hepatic CYP3A, but net inhibition still predominated. Ritonavir inhibits both intestinal and hepatic CYP3A and drug transport. Alfentanil miosis noninvasively determined CYP3A inhibition by ritonavir.

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.