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Induction of drug efflux protein expression by venlafaxine but not desvenlafaxine
Author(s) -
Bachmeier Corbin J.,
BeaulieuAbdelahad David,
Ganey Nowell J.,
Mullan Michael J.,
Levin Gary M.
Publication year - 2011
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.753
Subject(s) - p glycoprotein , pharmacology , efflux , venlafaxine , rhodamine 123 , chemistry , abcg2 , reuptake inhibitor , reuptake , transporter , biology , endocrinology , antidepressant , atp binding cassette transporter , serotonin , biochemistry , receptor , multiple drug resistance , hippocampus , gene , antibiotics
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 n M to 50 µ M ) 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 µ M ) 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. Copyright © 2011 John Wiley & Sons, Ltd.