Methadone metabolism and clearance are induced by nelfinavir despite inhibition of cytochrome P4503A (CYP3A) activity
| Autor: | Evan D. Kharasch, Alysa Walker, Dale Whittington, Pamela Sheffels Bedynek, Christine Hoffer |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Adolescent CYP2B6 Metabolic Clearance Rate CYP3A Administration Oral Pharmacology Toxicology Article Young Adult Pharmacokinetics Reference Values immune system diseases Humans Medicine Pharmacology (medical) Cross-Over Studies Nelfinavir Fexofenadine CYP3A4 business.industry Patient Selection virus diseases HIV Protease Inhibitors biochemical phenomena metabolism and nutrition Drug interaction Virology Analgesics Opioid Psychiatry and Mental health Injections Intravenous Cytochrome P-450 CYP3A Inhibitors business Methadone medicine.drug |
| Zdroj: | Drug and Alcohol Dependence. 101:158-168 |
| ISSN: | 0376-8716 |
| Popis: | Methadone plasma concentrations are decreased by nelfinavir. Methadone clearance and the drug interactions have been attributed to CYP3A4, but actual mechanisms of methadone clearance and the nelfinavir interaction are unknown. We assessed nelfinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A4/5 activity, and intestinal P-glycoprotein transport activity. CYP3A4/5 and transporters were assessed using alfentanil and fexofenadine, respectively.Twelve healthy HIV-negative volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral methadone. This was repeated after nelfinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by pupil diameter change (miosis).Nelfinavir decreased intravenous and oral methadone plasma concentrations 40-50%. Systemic clearance, hepatic clearance, and hepatic extraction all increased 1.6- and 2-fold, respectively, for R- and S-methadone; apparent oral clearance increased 1.7- and 1.9-fold. Nelfinavir stereoselectively increased (SR) methadone metabolism and metabolite formation clearance, and methadone renal clearance. Methadone bioavailability and P-glycoprotein activity were minimally affected. Nelfinavir decreased alfentanil systemic and apparent oral clearances 50 and 76%, respectively. Nelfinavir appeared to shift the methadone plasma concentration-effect (miosis) curve leftward and upward.Nelfinavir induced methadone clearance by increasing renal clearance, and more so by stereoselectively increasing hepatic metabolism, extraction and clearance. Induction occurred despite 50% inhibition of hepatic CYP3A4/5 activity and more than 75% inhibition of first-pass CYP3A4/5 activity, suggesting little or no role for CYP3A in clinical methadone disposition. Nelfinavir may alter methadone pharmacodynamics, increasing clinical effects. |
| Databáze: | OpenAIRE |
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