title: Effect of venlafaxine and desvenlafaxine on drug efflux protein expression and biodistribution in vivo.
abstract: Venlafaxine, and to a lesser extent desvenlafaxine, has previously been shown to induce the expression of the drug efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in whole cells and alter the cellular permeability of a known drug efflux probe (rhodamine 123). To validate these in vitro findings, wild-type mice were treated for 4 days with 10 mg/kg venlafaxine or desvenlafaxine, and drug efflux transporter expression was examined in the brain, liver, and intestine. P-gp and BCRP expression was significantly upregulated in the intestine, following a treatment with venlafaxine (2.6- and 6.7-fold, respectively) or desvenlafaxine (2.3- and 4.8-fold, respectively). In addition, venlafaxine increased the BCRP expression in the brain (40%) and liver (60%), whereas desvenlafaxine had no effect on drug efflux transporter levels in these tissues. Using the same treatment paradigm, we observed a minimal impact of either drug on the brain disposition of the known drug efflux probe, topotecan. However, in the periphery, venlafaxine treatment significantly reduced the topotecan oral bioavailability by nearly 40%, whereas the impact of desvenlafaxine on topotecan plasma levels was more modest (23%). These studies demonstrate an effect of venlafaxine on the drug efflux transport activity and the potential for clinical drug-drug interactions.
authors.affiliation: The Roskamp Institute Inc, Sarasota, Florida 34243.
authors.forename: Corbin
authors.initials: C
authors.lastname: Bachmeier
authors.forename: Gary M
authors.initials: GM
authors.lastname: Levin
authors.forename: David
authors.initials: D
authors.lastname: Beaulieu-Abdelahad
authors.forename: Jon
authors.initials: J
authors.lastname: Reed
authors.forename: Michael
authors.initials: M
authors.lastname: Mullan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport / Q000502:physiology; D001921:Brain / Q000378:metabolism; D003511:Cyclohexanols / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000069468:Desvenlafaxine Succinate; D004347:Drug Interactions / Q000502:physiology; D007408:Intestinal Absorption / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D014018:Tissue Distribution / Q000502:physiology*; D019772:Topotecan / Q000097:blood / Q000493:pharmacokinetics; D015854:Up-Regulation / Q000187:drug effects; 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; C501412:Abcg2 protein, mouse; D003511:Cyclohexanols; D000069470:Venlafaxine Hydrochloride; D019772:Topotecan; D000069468:Desvenlafaxine Succinate
keywords: P-glycoprotein; dose-response; drug interactions; drug transport; efflux pumps