Roskamp Institute Articles

February 14, 2011

Dr. Corbin Bachmeier of the Roskamp Institute and Dr. Gary Levin of the University of Southern Nevada recently published an article in Biopharmaceutics and Drug Disposition titled “Induction of drug efflux protein expression by venlafaxine but not desvenlafaxine”.  They observed that venlafaxine induced drug efflux protein expression in cell culture, whereas its metabolite, desvenlafaxine, had no impact on drug efflux protein levels.  They are currently exploring this phenomenon further in an in vivo paradigm through a grant provided by Pfizer.

Abstract

Venlafaxine and its metabolite desvenlafaxine are serotonin-norepinephrine reuptake inhibitors currently prescribed for the treatment of depression.  Previously, we reported venlafaxine is an inducer of MDR1, the gene responsible for P-glycoprotein (P-gp).  In the present study, we expanded upon these findings by examining the effect of venlafaxine and desvenlafaxine on the expression of both P-gp and the breast cancer resistance protein (BCRP) in human brain endothelial cells (HBMEC), an in vitro model of the blood-brain barrier (BBB).  The HBMEC were treated for 1 hour with various concentrations (500nM to 50µM) of venlafaxine and desvenlafaxine.  Western blot analysis revealed treatment with venlafaxine significantly induced the expression of P-gp (2-fold) and BCRP (1.75-fold) in a dose-dependent manner, while treatment with desvenlafaxine had no effect on drug efflux transporter expression.  To determine the functional significance of this effect, we examined the permeability of a known drug efflux probe, rhodamine 123, across the BBB model and Caco-2 cells, a model of intestinal absorption.  Treatment with venlafaxine (1µM to 50µM) for 1 hour significantly reduced the apical-to-basolateral permeability of R123 across the BBB model (30%) and Caco-2 cell monolayers (25%), indicative of increased drug efflux transporter expression at the apical membrane.  Conversely, desvenlafaxine had no effect on R123 permeability in either cellular model.  These studies indicate that venlafaxine, but not desvenlafaxine is an inducer of drug efflux transporter expression, which consequently increases the potential for clinical drug-drug interactions.  Therefore, based on these preliminary results, caution should be taken when prescribing venlafaxine with other P-gp substrates.

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