Diphenhydramine Alters the Disposition of Venlafaxine Through Inhibition of CYP2D6 Activity in Humans

Abstract

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.

Identification of Human Cytochrome P450 Isozymes Involved in Diphenhydramine N-Demethylation

“…In a previous case report, the half-life of diphenhydramine was 2-fold greater than the usual value in an elderly woman who had a prolonged half-life of imipramine (Glassman et al, 1985), which is mainly metabolized by CYP2D6 (Koyama et al, 1997), suggesting that diphenhydramine is a substrate of CYP2D6 in vivo. In addition, diphenhydramine is known to inhibit the metabolism of several other CYP2D6 substrates in vitro and in vivo (Hamelin et al, 1998(Hamelin et al, , 2000Lessard et al, 2001;He et al, 2002). These findings, coupled with the results of the present study, suggest that diphenhydramine is not only a potent inhibitor of CYP2D6 but also a high-affinity substrate of CYP2D6 in vitro and in vivo.…”

“…In fact, several classic antihistamines, such as chlorpheniramine, mequitazine, and promethazine, have been shown to be metabolized by CYP2D6 (Nakamura et al, 1996(Nakamura et al, , 1998Yasuda et al, 2001). In addition, previous studies revealed that diphenhydramine inhibited the metabolism of several CYP2D6 substrates in vivo and in vitro (Hamelin et al, 1998(Hamelin et al, , 2000Lessard et al, 2001;He et al, 2002). These findings suggest that the metabolism of diphenhydramine is also mediated by CYP2D6.…”

“…However, Lessard et al (2001) reported that the clearance of diphenhydramine to its N-demethylated metabolite (2-benzhydryloxy-N-methyl-ethanamine) is not different in extensive and poor metabolizer phenotypes of CYP2D6 and suggested that diphenhydramine is not extensively metabolized by this P450 isozyme. In addition, multiple P450 isozymes, CYP1A2, CYP2C18, CYP2C19, CYP2D6, and CYP2B6, have been reported to be involved in the N-demethylation of diphenhydramine at 20 M Sharma and Hame-lin, 2003).…”

Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood

“…Several drugs detected during the routine drug screening are metabolized by CYP2D6. Patients who are CYP2D6 PMs, or are taking drugs that may interact, may receive concentrations in the range of those found in overdose when taking therapeutic doses [20,55]. Thus, drug interactions involving VEN may have occurred in several of the cases included in the present study.…”

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

“…The SSRIs are twice as effective as the "placebo" effect at reducing menopausal symptoms in randomized clinical trials [138][139][140], so there is naturally an increased usage of SSRIs with long-term tamoxifen treatment to maintain compliance. Unfortunately, the metabolism of tamoxifen to hydroxylated metabolites [141][142][143] and the metabolism of SSRIs [39,[144][145][146][147] both occur via the CYP2D6 gene product. Indeed Stearns and coworkers [97] showed that the SSRI inhibitor paroxetine reduced the levels of endoxifen during adjuvant tamoxifen therapy and endoxifen levels decrease by 64% in women with wild type CYP2D6 enzyme.…”