Mechanism of Ritonavir Changes in Methadone Pharmacokinetics and Pharmacodynamics: II. Ritonavir Effects on CYP3A and P-Glycoprotein Activities

Abstract

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.

Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir

“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 F o r P e e r R e v i e w 13 The possibility of drug-drug interactions must be considered in the treatment of HIV-associated pain. In previous pharmacokinetic studies in healthy volunteers, for instance, the oral bioavailability of alfentanil was increased from 37% to 95% by steady-state ritonavir concentrations [18]. The acute administration of ritonavir reduced the clearance of intravenous fentanyl by 67% [16].…”

“…Ritonavir has been shown to be a strong inhibitor of CYP3A both in vitro [38,39] and in vivo [16,18,40,41]. In the present study ritonavir caused a 3-fold mean increase of oxycodone AUC 0-∞ , which is somewhat smaller than that observed after the azole antimycotic voriconazole (3.6-fold increase in oxycodone AUC 0-∞ ), but bigger than that observed for itrazonazole (2.4-fold increase) and telithromycin (1.8-fold increase) [25][26][27].…”

“…Ritonavir is a potent CYP3A, CYP2D6 and P-glycoprotein inhibitor [16][17][18]. It has been described to induce CYP1A2, CYP2B6, CYP2C9 and CYP2C19 [19,20].…”

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

“…Hepatic CYP3A activity was evaluated on day 2 using i.v. alfentanil as an in vivo probe (Kharasch et al, 2004b(Kharasch et al, , 2008b(Kharasch et al, , 2009a(Kharasch et al, ,b, 2011a(Kharasch et al, ,b, 2012a. Subjects received ondansetron followed 30 minutes later by alfentanil bolus (15 and 5 mg/kg at control and ritonavir-lopinavir sessions, respectively).…”

“…First-pass CYP3A activity and intestinal P-gp (and other transporters) activity were evaluated on day 1 using oral alfentanil and fexofenadine as in vivo probes (Kharasch et al, 2004b(Kharasch et al, , 2005(Kharasch et al, , 2008b(Kharasch et al, , 2009a(Kharasch et al, ,b, 2011a(Kharasch et al, ,b, 2012a. Subjects received ondansetron (4 mg i.v.)…”