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Mechanism of Ritonavir Changes in Methadone Pharmacokinetics and Pharmacodynamics: II. Ritonavir Effects on CYP3A and P‐Glycoprotein Activities
Author(s) -
Kharasch ED,
Bedynek PS,
Walker A,
Whittington D,
Hoffer C
Publication year - 2008
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2008.102
Subject(s) - ritonavir , pharmacology , cyp3a , pharmacokinetics , fexofenadine , pharmacodynamics , chemistry , methadone , p glycoprotein , medicine , metabolism , immunology , biochemistry , viral load , cytochrome p450 , human immunodeficiency virus (hiv) , antiretroviral therapy , multiple drug resistance , antibiotics
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–∞ /dose ratio (ritonavir/control) for oral ALF 25‐fold. Steady‐state ritonavir increased the AUC 0–∞ /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–∞ 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. Clinical Pharmacology & Therapeutics (2008); 84 , 4, 506–512 doi: 10.1038/clpt.2008.102