title: Sertraline alters multidrug resistance phosphoglycoprotein activity in the mouse placenta and fetal blood-brain barrier.
abstract: Phosphoglycoprotein (P-gp) is highly expressed in the placental syncytiotrophoblast and prevents xenobiotics from entering the fetus. In tumor cells, P-gp-mediated substrate efflux is inhibited by selective serotonin reuptake inhibitors (SSRIs). However, nothing is known regarding the effects of SSRIs on P-gp function in the placenta or fetal tissues. We hypothesized that the SSRI sertraline would decrease P-gp-mediated drug efflux at the placenta and fetal blood-brain barrier (BBB)-increasing P-gp substrate transfer from the mother to the fetus and fetal brain. In contrast to our hypothesis, this study presents the novel findings that sertraline (4 hours exposure) increases placental P-gp-mediated efflux (P < .001), resulting in decreased drug transfer to the fetus. Meanwhile, sertraline decreases fetal (P < .001) and maternal (P < .05) BBB P-gp-mediated efflux, resulting in increased drug transfer into the fetal and maternal brain from the circulation. This suggests that P-gp regulation by sertraline is tissue specific. These findings have important clinical implications with respect to fetal protection during maternal drug therapy in pregnancy.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Manzerul
authors.initials: M
authors.lastname: Bhuiyan
authors.forename: Sophie
authors.initials: S
authors.lastname: Petropoulos
authors.forename: William
authors.initials: W
authors.lastname: Gibb
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Matthews
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D004077:Digoxin / Q000378:metabolism; D005260:Female; D005333:Fetus; D008297:Male; D008353:Mannitol / Q000378:metabolism; D051379:Mice; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D020280:Sertraline / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004077:Digoxin; D008353:Mannitol; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline