Sertraline Alters Multidrug Resistance Phosphoglycoprotein Activity in the Mouse Placenta and Fetal Blood–Brain Barrier

• Published in: Reproductive sciences (Thousand Oaks, Calif.) Calif.), 2012-04, Vol.19 (4), p.407-415
• Main Authors: Bhuiyan, Manzerul, Petropoulos, Sophie, Gibb, William, Matthews, Stephen G.
• Format: Article
• Language: English
• Subjects: Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Biological Transport; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain; Digoxin - metabolism; Drugs; Embryology; Female; Fetus; Fetuses; Gynecology. Andrology. Obstetrics; Male; Mannitol - metabolism; Medical sciences; Medicine & Public Health; Mice; Multidrug resistance; Neuropharmacology; Obstetrics/Perinatology/Midwifery; Pharmacology. Drug treatments; phosphoglycoprotein; Placenta; Placenta - drug effects; Placenta - metabolism; Pregnancy; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Reproductive Medicine; Serotonin uptake inhibitors; Serotonin Uptake Inhibitors - pharmacology; sertraline; Sertraline - pharmacology; Tumor cells; Xenobiotics
• ISSN: 1933-7191; 1933-7205
• DOI: 10.1177/1933719111424438

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.