Diphenhydramine Alters the Disposition of Venlafaxine Through Inhibition of CYP2D6 Activity in Humans
| Autor: | Bettina A. Hamelin, Jacques Turgeon, Gilles O'Hara, Caroline Gauvin, M.A. Yessine, Line Labbé, Etienne Lessard, Jacynthe Leblanc |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Adult
Male medicine.medical_specialty Genotype Diphenhydramine hydrochloride medicine.medical_treatment Venlafaxine Hydrochloride Venlafaxine Pharmacology Pharmacokinetics Oral administration Cytochrome P-450 CYP2D6 Inhibitors Internal medicine medicine Humans Drug Interactions Pharmacology (medical) Enzyme Inhibitors Analysis of Variance Chemistry Diphenhydramine Drug interaction Cyclohexanols Psychiatry and Mental health Phenotype Endocrinology Cytochrome P-450 CYP2D6 Histamine H1 Antagonists Antidepressive Agents Second-Generation Antihistamine medicine.drug |
| Zdroj: | Journal of Clinical Psychopharmacology. 21:175-184 |
| ISSN: | 0271-0749 |
| DOI: | 10.1097/00004714-200104000-00009 |
| Popis: | CYP2D6 is the major enzyme involved in the metabolism of venlafaxine. Subjects with a low CYP2D6 activity have increased plasma concentrations of venlafaxine that may predispose them to cardiovascular side effects. In vitro and in vivo studies showed that diphenhydramine, a nonprescription antihistamine, can inhibit CYP2D6 activity. Therefore, the authors investigated in this study a potential drug interaction between diphenhydramine and venlafaxine. Fifteen male volunteers, nine with the extensive metabolizer (EM) and six with the poor metabolizer (PM) phenotype of CYP2D6, received venlafaxine hydrochloride 18.75 mg orally every 12 hours for 48 hours on two occasions (1 week apart): once alone and once during the concomitant administration of diphenhydramine hydrochloride (50 mg every 12 hours). Blood and urine samples were collected for 12 hours under steady-state conditions. In EMs, diphenhydramine decreased venlafaxine oral clearance from 104+/-60 L/hr to 43+/-23 L/hr (mean +/- SD; p < 0.05) without any effect on renal clearance (4+/-1 L/hr during venlafaxine alone and 4+/-2 L/hr during venlafaxine plus diphenhydramine). In PMs, coadministration of diphenhydramine did not cause significant changes in oral clearance and partial metabolic clearances of venlafaxine to its various metabolites. Diphenhydramine disposition was only slightly affected by genetically determined low CYP2D6 activity or concomitant administration of venlafaxine. In conclusion, diphenhydramine, at therapeutic doses, inhibits CYP2D6-mediated metabolism of venlafaxine in humans. Clinically significant interactions could be encountered during the concomitant administration of diphenhydramine and other antidepressant or antipsychotic drugs that are substrates of CYP2D6. |
| Databáze: | OpenAIRE |
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