Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans

CYP2D6 is the major enzyme involved in the metabolism of venlafaxine. Subje cts with a low CYP2D6 activity have increased plasma concentrations of venl afaxine that may predispose them to cardiovascular side effects. In vitro a nd in vivo studies showed that diphenhydramine, a nonprescription antihista mine, can inhibit CYP2D6 activity. Therefore, the authors investigated in t his study a potential drug interaction between diphenhydramine and venlafax ine. Fifteen male volunteers, nine with the extensive metabolizer (EM) and six with the poor metabolizer (PM) phenotype of CYP2D6, received venlafaxin e hydrochloride 18.75 mg orally every 12 hours for 48 hours on two occasion s (1 week apart): once alone and once during the concomitant administration of diphenhydramine hydrochloride (50 mg every 12 hours). Blood and urine s amples were collected for 12 hours under steady-state conditions. In EMs, d iphenhydramine decreased venlafaxine oral clearance from 104 +/- 60 L/hr to 43 +/- 23 L/hr (mean +/- SD; p < 0.05) without any effect on renal clearan ce (4 <plus/minus> 1 L/hr during venlafaxine alone and 4 +/- 2 L/hr during venlafaxine plus diphenhydramine). In PMs, coadministration of diphenhydram ine did not cause significant changes in oral clearance and partial metabol ic clearances of venlafaxine to its various metabolites. Diphenhydramine di sposition was only slightly affected by genetically determined low CYP2D6 a ctivity or concomitant administration of venlafaxine. In conclusion, diphen hydramine, at therapeutic doses, inhibits CYP2D6-mediated metabolism of ven lafaxine in humans. Clinically significant interactions could be encountere d during the concomitant administration of diphenhydramine and other antide pressant or antipsychotic drugs that are substrates of CYP2D6.