While the importance of P-glycoprotein (P-gp) in determining drug disposition has been well recognized, the role of Breast Cancer Resistance Protein (BCRP) in this regard has just begun to be realized. Both P-gp and BCRP are expressed in the apical membranes of small intestinal epithelium, the liver canalicular membranes, and the placental syncytiotrophoblasts. Thus, it is not surprising that BCRP, like P-gp, affects the bioavailability and fetal distribution of drugs. Pregnant women are routinely administered various drugs such as antivirals, anti-epileptics, antibiotics, anti-hypertensives, and anti-histamines. Many of these drugs are substrates or modulators of P-gp. As BCRP and P-gp have considerable degree of substrate overlap, many of these drugs are also likely to be substrates of BCRP. In order to assess if BCRP plays an important role in determining the safety and bioavailability of drugs given during pregnancy, it is critical that we first determine which of the drugs routinely administered to pregnant women are substrates of BCRP. BCRP has the highest expression levels in the placenta where it functions, like P-gp, to protect the fetus from Xenobiotics. Preliminary data from our laboratories indicate that expression of both BCRP and P-gp in the placenta is gestational-age dependent, suggesting regulation by pregnancy-specific hormones. The Hypothesis and Specific Aims outlined below are designed to address these clinically relevant questions. Hypothesis: BCRP and placental P-gp activity and expression is up-regulated during pregnancy and alters the absorption, distribution (including across the placenta), and elimination of drugs BCRP and P-gp substrates) routinely administered to pregnant women. To test the above hypothesis we will determine: 1. If drugs routinely administered to pregnant women (e.g., anti-HIV protease inhibitors, anti-epileptic drugs, antibiotics, ani-hypertensives and antihistamines) are high-affinity substrates of BCRP. 2. If in vitro and in vivo expression of BCRP and P-gp is regulated by pregnancy-specific hormones. 3. The molecular mechanism by which BCRP and P-gp expression is regulated by pregnancy-specific hormones. 4. If the in vivo absorption and fetal distribution of a high-affinity BCRP substrates (routinely administered to pregnant women) is affected y pregnancy in P-gp-deficient mice.
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