Transport of glyburide by placental ABC transporters: implications in fetal drug exposure.
Much evidence has demonstrated that a number of ATP-binding cassette (ABC) efflux transporters including P-glycoprotein (PGP), the multidrug resistance-associated proteins (MRPs) and the breast cancer resistance protein (BCRP) are highly expressed in placental tissues and are believed to profoundly limit the passage of therapeutic or toxic xenobiotics to the fetus. Recent studies indicate that the oral hypoglycemic glyburide does not cross the human placenta to an appreciable extent. Our objective was to identify placental transporters potentially involved in limiting the transplacental transfer of glyburide to the fetus. Thus, [(3)H]-glyburide transport was examined in BCRP, PGP, MRP1, MRP2 and MRP3 over-expressing cell lines in the presence or absence of specific inhibitors. Our results demonstrated significant increases in the intracellular accumulation of [(3)H]-glyburide in BCRP and MRP3 over-expressing cells in the presence of the inhibitors novobiocin and indomethacin, respectively. PGP inhibition with verapamil or MRP inhibition with indomethacin did not affect [(3)H]-glyburide accumulation in the PGP or MRP2 over-expressing cell lines and only limited changes were seen in the MRP1 over-expressing cell line. On the other hand, glyburide was found to significantly inhibit MRP1-, MRP2- and MRP3-mediated efflux of 5-carboxyfluorescein diacetate and PGP-mediated transport of rhodamine 123. Our evidence is the first to clearly indicate that glyburide is preferentially transported by BCRP and MRP3.
Gedeon
C
C
Hospital for Sick Children, Toronto, Ontario, Canada.
Behravan
J
J
Koren
G
G
Piquette-Miller
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005260:Female; D005452:Fluoresceins / Q000378:metabolism; D005905:Glyburide / Q000378:metabolism*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000378:metabolism; D008942:Mitoxantrone / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009675:Novobiocin / Q000494:pharmacology; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D020112:Rhodamine 123 / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D005452:Fluoresceins; D005905:Glyburide; D007213:Indomethacin; D026901:Membrane Transport Proteins; D008942:Mitoxantrone; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D009675:Novobiocin; D020112:Rhodamine 123; D014700:Verapamil; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C114462:multidrug resistance-associated protein 3; C084577:5-carboxyfluorescein diacetate; C421109:multidrug resistance-associated protein 1