Breast cancer resistance protein (BCRP/ABCG2) is a member of the ATP-binding cassette transporter family that recognizes a variety of chemically unrelated compounds. Its expression has been revealed in many mammal tissues, including placenta. The purpose of this study was to describe its role in transplacental pharmacokinetics using rat placental HRP-1 cell line and dually perfused rat placenta. In HRP-1 cells, expression of Bcrp, but not P-glycoprotein, was revealed at mRNA and protein levels. Cell accumulation studies confirmed Bcrp-dependent uptake of BODIPY FL prazosin. In the placental perfusion studies, a pharmacokinetic model was applied to distinguish between passive and Bcrp-mediated transplacental passage of cimetidine as a model substrate. Bcrp was shown to act in a concentration-dependent manner and to hinder maternal-tofetal transport of the drug. Fetal-to-maternal clearance of cimetidine was found to be 25 times higher than that in the opposite direction; this asymmetry was partly eliminated by BCRP inhibitors fumitremorgin C (2 M) or N- (4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918; 2 M) and abolished at high cimetidine concentrations (1000 M). When fetal perfusate was recirculated, Bcrp was found to actively remove cimetidine from the fetal compartment to the maternal compartment even against a concentration gradient and to establish a 2-fold maternal-to-fetal concentration ratio. Based on our results, we propose a two-level defensive role of Bcrp in the rat placenta in which the transporter 1) reduces passage of its substrates from mother to fetus but also 2) removes the drug already present in the fetal circulation.Placenta is an organ that brings maternal and fetal blood circulations into proximity, allowing mutual interchange of nutrients and waste products. Conversely, placenta forms a barrier to protect the fetus against harmful endo-and exogenous compounds from maternal circulation. As a barrier, the human and rodent placenta had for long been supposed to present only a mechanical obstruction formed by fetal endothelia, basal membranes, and syncytiotrophoblast. However, over the past two decades, a variety of metabolizing enzymes and drug efflux transporters of the ATP-binding cassette (ABC) transporter family have been localized in placental trophoblast (Marin et al., 2004;Syme et al., 2004). These proteins are thought to strengthen, in an active and capacitylimited manner, placental barrier role and help in protecting the fetus.Drug efflux transporters of the ABC family are membraneembedded proteins that limit intracellular concentration of substrates by pumping them out of cell through an active, energy-dependent mechanism (Schinkel and Jonker, 2003). The most intensively studied drug efflux transporters to date have been P-glycoprotein (P-gp; ABCB1), breast cancer resistance protein (BCRP; ABCG2) and multidrug resistance-associated proteins 1 and 2 (ABCC1 and ABCC2), all of which were found t...
