Program Summary

Drugs are administered to pregnant women, and therefore their fetuses, without the necessary clinical data about the pharmacokinetics (i.e. how the drug is handled by the body), dose, safety, or efficacy of the drugs in these vulnerable populations. To determine the correct dose of a drug to administer to the pregnant woman, it is important to know if the pharmacokinetics of the drug are different in pregnant women when compared with men or nonpregnant women. Our research will focus on one of two major routes of drug disposition, namely drug transport. Drug transport is a study of how drugs are moved from without the cell to within the cell or vice-versa. We will test the following overarching and unifying hypothesis: Expression and activity of influx and efflux transporters is higher during pregnancy to respectively meet the increased need of nutrients by the mother and her fetus and to minimize toxicityfrom foreign chemicals such as drugs.

The transporters we will study are those likely to be quantitatively most important in drug transport in both the intestine and the placenta, namely: P-glycoprotein (P-gp; Project 1), the Breast Cancer Resistance Protein (BCRP; Project 2), and the Organic Cation Transporter 3 (OCT3; Project 3). In the placenta, P-glycoprotein and BCRP participate in the efflux of drugs, thus protecting the fetus from toxic effects of drugs, while OCT3 functions to allow the entry of endogenous compounds (and drugs) into the fetal circulation. In contrast, all three transporters play a role in the elimination of drugs in the liver and intestine. Moreover, all three transporters transport similar but distinct drugs used in the treatment of a variety of diseases. Studies outlined in the three projects will elucidate the interplay among these three transporters in how they affect maternal AND fetal exposure to drugs. Therefore, the three projects will pursue a single goal of elucidating mechanisms by which drug transporters alter maternal and fetal drug exposure during pregnancy. Results obtained from these studies will have wide-ranging consequences for drug use during pregnancy.

Project 1 - P-glycoprotein (P-gp) & Cytochrome P450 3A4/5 (CYP3A4/5)

Project 2 - Breast Cancer Resistance Protein (BCRP, ABCG2)

Project 3 - Organic Cation Transporter 3 (OCT3)