Gestational Age Variation in Human Placental Transport Mechanisms

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DESCRIPTION (provided by applicant): Exposure to drugs is a lifelong experience that begins in utero. Across the lifespan, from birth to extreme old age, the normal gestational period of approximately 37 weeks is the least understood period of drug disposition. The exposure of pregnant women to psychoactive drugs, regarded as medically necessary to maintain maternal health for a variety of mental disorders, and the exposure to illegal drugs, are critical public health care issues. Drug exposure of the fetus during pregnancy can have life-long pharmacodynamic consequences. Multiple transporter proteins have been shown to be involved in the passage of ions, nutrients, drugs, and other chemicals across the placental membranes in a bi-directional fashion. There exists a paucity of data related to the function of placental drug transporters to inform clinical practice regarding the selection and use of drugs that are transporter substrates. This grant application proposes studies in obstetrical pharmacology from three highly experienced Co-Principal Investigators to improve our ability to guide the use of drugs during pregnancy. Three specific aims are proposed to substantially enhance our knowledge of the placenta across human gestation and improve our understanding of the role of major drug transporters in regulating fetal drug exposure. Accordingly, we have chosen five major transporters for study: the ABCB1 gene encoded multi-drug resistance protein or P-glycoprotein (P-gp); ABCC3 gene encoded multidrug resistance protein (MRP3); ABCG2 gene encoded Breast Cancer Resistance Protein (BCRP); SLC6A2 gene encoded norepinephrine transporter (NET); and SLC6A4 gene encoded serotonin transporter (SERT). Specific aim 1 will define gestational age dependant changes in protein expression and functional activity of each transporter. Specific Aim 2 will define 1st, early 2nd, and 3rd trimester exposure to substrates of these transporters. Specific Aim 3 will benefit from the insight gained from aims 1 and 2 in the development of a physiologically- based pharmacokinetic model to predict placental drug transfer and fetal drug exposure using patient-specific characteristics. The availability of health placental tissue for study, representing all three trimesters, allows a unique opportunity to conduct this innovative research. The results will be significant in providing highly relevant data for understanding how drugs pass from the mother to her fetus at different periods of human gestation. PUBLIC HEALTH RELEVANCE: This research study will add significantly to the understanding of maternal fetal passage of psychoactive medications in pregnant women across gestation. Results will aid clinicians in selecting those medications that preserve maternal health while having the minimum impact on the developing fetus. Improved treatment of mental illness in pregnancy will improve both maternal and child health.