The role of placental breast cancer resistance protein in the efflux of glyburide across the human placenta.
Gestational diabetes mellitus is a common medical complication in pregnancy. Recent findings demonstrate that glyburide is effluxed against a concentration gradient from the fetal to the maternal circulation. However, the transport systems involved in the active efflux of glyburide in the human placenta have not yet been identified. The ATP-binding cassette transporter, breast cancer resistance protein (BCRP), is highly expressed in placental syncytiotrophoblast suggesting it may play a role in protecting the fetus from drug toxicity. The objective of the present study was to determine whether BCRP participates in the transport of glyburide across the human placenta. The placental transfer of glyburide in the presence of specific BCRP inhibitor, nicardipine, was investigated using the ex vivo dual perfusion system of isolated human placental lobules. In a closed experiment, glyburide was added (200 ng/mL) to the maternal and fetal circulations and the BCRP inhibitor (20 microM) was added to the maternal circulation. Samples were taken during pre-control, experimental, and post-control periods for measurement of glyburide and markers of tissue viability. Results obtained from perfusions (n=4) in the presence of the BCRP inhibitor show a significant increase in the mean fetal-to-maternal concentration ratio of glyburide determined at 180 min, 0.56+/-0.06, when compared to the mean ratio obtained in the absence of inhibitor, 0.32+/-0.06 (p=0.04). These data indicate that nicardipine partially blocked the transfer of glyburide across the whole placenta through its inhibition of BCRP. This is the first ex vivo evidence that BCRP actively transports glyburide.
The Hospital for Sick Children, Division of Clinical Pharmacology and Toxicology, Toronto, Ontario, Canada.
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Pollex
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Lubetsky
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Koren
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005260:Female; D005905:Glyburide / Q000493:pharmacokinetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009529:Nicardipine / Q000494:pharmacology; D009924:Organ Culture Techniques; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D007004:Hypoglycemic Agents; D009363:Neoplasm Proteins; D009529:Nicardipine; D005905:Glyburide