The breast cancer resistance protein (Bcrp1/Abcg2) limits fetal distribution of glyburide in the pregnant mouse: an Obstetric-Fetal Pharmacology Research Unit Network and University of Washington Specialized Center of Research Study.
Breast cancer resistance protein (BCRP) is most abundantly expressed in the apical membrane of placental syncytiotrophoblasts, suggesting that it may protect the fetus by impeding drug penetration across the placental barrier. Glyburide (GLB) is an antidiabetic drug routinely used to treat gestational diabetes. In this study, we first determined whether GLB is a BCRP/Bcrp1 substrate. The intracellular [(3)H]GLB concentrations in Madin-Darby canine kidney (MDCK)/BCRP cells were significantly lower than those in MDCK/vector cells. The addition of 10 muM fumitremorgin C, a specific BCRP inhibitor, significantly increased the intracellular [(3)H]GLB concentrations approximately 2-fold in MDCK/BCRP cells, but it had no effect in MDCK/vector cells. Similar results were obtained using MDCKII parent and MDCKII/Bcrp1 cells. GLB was also shown to be a BCRP/Bcrp1 substrate in transwell transport experiments. We then examined whether Bcrp1 limits fetal distribution of GLB in the pregnant mouse. GLB was administered by retro-orbital injection to the wild-type and Bcrp1(-/-) pregnant mice. The maternal plasma samples and fetuses were collected at various times (0.5-240 min) after drug administration. The GLB concentrations in the maternal plasma samples and homogenates of fetal tissues were determined by high-performance liquid chromatography/mass spectrometry. Although the maternal plasma area under the concentration-time curves (AUCs) of GLB in the wild-type and Bcrp1(-/-) pregnant mice were comparable, the fetal AUC of GLB in the Bcrp1(-/-) pregnant mice was approximately 2 times greater than that in the wild-type pregnant mice. These results suggest that GLB is a BCRP/Bcrp1 substrate, and Bcrp1 significantly limits fetal distribution of GLB in the pregnant mouse, but it has only a minor effect on the systemic clearance of the drug.
Zhou
Lin
L
Department of Pharmaceutics, School of Pharmacy, Box 357610, University of Washington, Seattle, WA 98195, USA.
Naraharisetti
Suresh Babu
SB
Wang
Honggang
H
Unadkat
Jashvant D
JD
Hebert
Mary F
MF
Mao
Qingcheng
Q
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D018929:Cell Culture Techniques; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D003627:Data Interpretation, Statistical; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000378:metabolism*; D005905:Glyburide / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007275:Injections, Intravenous; D007668:Kidney / Q000166:cytology; D008431:Maternal-Fetal Exchange; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D011247:Pregnancy; D013379:Substrate Specificity; D014162:Transfection
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D018076:DNA, Complementary; D007211:Indoles; C010522:tryptoquivaline; D005905:Glyburide