Received for publication September 6, 2007.
Revised November 22, 2007.
Accepted for publication December 12, 2007.

The Breast Cancer Resistance Protein (Bcrp1/Abcg2) Limits Fetal Distribution of Glyburide in the Pregnant Mouse - An OPRU Network and UW SCOR Study

Abstract

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 examined if GLB is a BCRP/Bcrp1 substrate. The intracellular [³H]-GLB concentrations in MDCK/BCRP cells were significantly lower than those in MDCK/vector cells. The addition of 10 µM FTC, a specific BCRP inhibitor, significantly increased the intracellular [³H]-GLB concentrations approximately 2-fold in MDCK/BCRP cells, but had no effect on those 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 if 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 HPLC/MS. While the maternal plasma 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 has only a minor effect on the systemic clearance of the drug.

Key words: MDR/p-Glycoprotein, Liver transporters

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