title: Carrier-mediated placental transport of cimetidine and valproic acid across differentiating JEG-3 cell layers.
abstract: Human choriocarcinoma has been used as a model to study trophoblast transcellular drug transport in the placenta. Previous models had limitations regarding low molecular weight drug transport through the intracellular gap junction. The purpose of this study was to evaluate placental carrier-mediated transport across a differentiating JEG-3 choriocarcinoma cell (DJEGs) layer model in which the intracellular gap junction was restricted. Cimetidine is the substrate of an efflux transporter, breast cancer resistance protein (BCRP). BCRP highly expressed in the placenta, and its function in the DJEGs model was investigated. In addition, the placental drug transport of another efflux transporter, multidrug resistance-associated proteins (MRPs), and an influx transporter, monocarboxylate transporter (MCT), were examined with various substrates. Cimetidine permeated from the fetal side to the maternal side at significantly high levels and saturated in a dose-dependent manner. The permeability coefficient of a MRP substrate, fluorescein, across the DJEGs model was significantly increased by inhibiting MRP function with probenecid. On the other hand, permeation in the influx direction to the fetal side with a substrate of MCT, valproic acid, had a gentle dose-dependent saturation. These findings suggest that the DJEGs model could be used to evaluate transcellular placental drug transport mediated by major placental transporters.
authors.forename: K
authors.initials: K
authors.lastname: Ikeda
authors.forename: C
authors.initials: C
authors.lastname: Ueda
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.forename: A
authors.initials: A
authors.lastname: Nakamura
authors.forename: Y
authors.initials: Y
authors.lastname: Hatsuda
authors.forename: S
authors.initials: S
authors.lastname: Kawanishi
authors.forename: S
authors.initials: S
authors.lastname: Nishii
authors.forename: M
authors.initials: M
authors.lastname: Ogawa
mesh_terms: D000328:Adult; D000465:Algorithms; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D002927:Cimetidine / Q000493:pharmacokinetics*; D005260:Female; D019793:Fluorescein; D006635:Histamine H2 Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D014635:Valproic Acid / Q000493:pharmacokinetics*
chemical_list: D000927:Anticonvulsants; D002352:Carrier Proteins; D006635:Histamine H2 Antagonists; D014635:Valproic Acid; D002927:Cimetidine; D019793:Fluorescein