title: Induction of drug efflux protein expression by venlafaxine but not desvenlafaxine.
abstract: Venlafaxine and its metabolite desvenlafaxine are serotonin-norepinephrine reuptake inhibitors currently prescribed for the treatment of depression. Previously, it was reported that venlafaxine is an inducer of MDR1, the gene responsible for P-glycoprotein (P-gp). The present study 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 h with various concentrations (500 nM to 50 µM) 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, the permeability of a known drug efflux probe, rhodamine 123, across the BBB model and Caco-2 cells, a model of intestinal absorption, were examined. Treatment with venlafaxine (1-50 µM) for 1 h 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.
authors: The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA.
authors: Corbin J
authors: CJ
authors: Bachmeier
authors: David
authors: D
authors: Beaulieu-Abdelahad
authors: Nowell J
authors: NJ
authors: Ganey
authors: Michael J
authors: MJ
authors: Mullan
authors: Gary M
authors: GM
authors: Levin
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000187:drug effects; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D003511:Cyclohexanols / Q000494:pharmacology* / Q000633:toxicity; D000069468:Desvenlafaxine Succinate; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D042783:Endothelial Cells; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000187:drug effects; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D012293:Rifampin / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D000069470:Venlafaxine Hydrochloride
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D003511:Cyclohexanols; D000069468:Desvenlafaxine Succinate; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D009363:Neoplasm Proteins; D020112:Rhodamine 123; D012293:Rifampin; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride; C116614:ABCG2 protein, human