Received for publication August 6, 2007.
Revised August 23, 2007.
Accepted for publication August 30, 2007.

Bcrp1 Limits Fetal Distribution of Nitrofurantoin in the Pregnant Mouse

Abstract

The efflux transporter, the breast cancer resistance protein (BCRP), is most abundantly expressed in the apical membrane of the placental syncytiotrophoblasts, indicating that it could play an important role in protecting the fetus by limiting xenobiotic/drug penetration across the placental barrier. In the present study, we examined if Bcrp1, the murine homolog of human BCRP, limits fetal distribution of the model BCRP/Bcrp1 substrate, nitrofurantoin (NFT), in the pregnant mouse. NFT was intravenously administered to the FVB wild-type and Bcrp1-/- pregnant mice. The maternal plasma samples and fetuses were collected at various times (5-60 min) after drug administration. The NFT concentrations in the maternal plasma samples and homogenates of fetal tissues were determined by HPLC/UV. While the maternal plasma area under concentration-time curve (AUC) of NFT in the Bcrp1-/- pregnant mice (97.4 ± 10.0 µg • min/ml plasma) was only slightly (but significantly) higher than that in the wild-type pregnant mice (78.4 ± 6.0 µg • min/ml plasma), the fetal AUC of NFT in the Bcrp1-/- pregnant mice (1493.0 ± 235.3 ng • min/g fetus) was approximately 5 times greater than that in the wild-type pregnant mice (298.6 ± 77.4 ng • min/g fetus). These results clearly suggest that Bcrp1 significantly limits fetal distribution of NFT in the pregnant mouse, but has only a minor effect on the systemic clearance of the drug.

Key words: ABC transporters, drug transport, fetal drug metabolism, fetal toxicology