Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: II. Ritonavir effects on CYP3A and P-glycoprotein activities

Clin Pharmacol Ther. 2008 Oct;84(4):506-12. doi: 10.1038/clpt.2008.102.

Abstract

Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. We determined short-term (2-day) and steady-state (2-week) ritonavir effects on intestinal and hepatic CYP3A4/5 (probed with intravenous (IV) and oral alfentanil (ALF) and with miosis) and P-glycoprotein (P-gp) (fexofenadine), and on methadone pharmacokinetics and pharmacodynamics in healthy volunteers. Acute ritonavir increased the area under the concentration-time curve (AUC)(0-infinity)/dose ratio (ritonavir/control) for oral ALF 25-fold. Steady-state ritonavir increased the AUC(0-Infinity)/dose ratio for IV and oral ALF 4- and 10-fold, respectively; reduced hepatic extraction (from 0.26 to 0.07) and intestinal extraction (from 0.51 to 0); and increased bioavailability (from 37 to 95%). Acute ritonavir inhibits first-pass CYP3A > 96%. Chronic ritonavir inhibits hepatic CYP3A (> 70%) and first-pass CYP3A (> 90%). Acute and steady-state ritonavir increased the fexofenadine AUC(0-infinity) 2.8- and 1.4-fold, respectively, suggesting P-gp inhibition. Steady-state compared with acute ritonavir caused mild apparent induction of P-gp and hepatic CYP3A, but net inhibition still predominated. Ritonavir inhibited both intestinal and hepatic CYP3A and drug transport. ALF miosis noninvasively determined CYP3A inhibition by ritonavir.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Adult
  • Alfentanil / administration & dosage
  • Alfentanil / blood
  • Alfentanil / pharmacokinetics
  • Area Under Curve
  • Biological Availability
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A / physiology*
  • Cytochrome P-450 CYP3A Inhibitors
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Female
  • HIV Protease Inhibitors / pharmacokinetics
  • HIV Protease Inhibitors / pharmacology*
  • Humans
  • Intestines / enzymology
  • Liver / enzymology
  • Male
  • Methadone / pharmacokinetics*
  • Methadone / pharmacology
  • Narcotics / pharmacokinetics*
  • Narcotics / pharmacology
  • Pupil / drug effects
  • Ritonavir / pharmacokinetics
  • Ritonavir / pharmacology*
  • Stereoisomerism
  • Terfenadine / administration & dosage
  • Terfenadine / analogs & derivatives
  • Terfenadine / blood
  • Terfenadine / pharmacokinetics

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Cytochrome P-450 CYP3A Inhibitors
  • HIV Protease Inhibitors
  • Narcotics
  • Alfentanil
  • Terfenadine
  • fexofenadine
  • Cytochrome P-450 CYP3A
  • Ritonavir
  • Methadone