Gestational Age Variation in Human Placental Transport Mechanisms

描述（由申请人提供）：接触药物是一种终生的经历，从子宫开始。在整个生命周期中，从出生到老年，大约37周的正常妊娠期是药物处置最不为人所知的时期。孕妇接触精神活性药物和接触非法药物是严重的公共卫生保健问题，从医学上讲，这些药物被认为是维持产妇对各种精神障碍的健康所必需的。胎儿在怀孕期间的药物暴露会产生终生的药效学影响。多种转运蛋白以双向方式参与离子、营养物质、药物和其他化学物质在胎盘膜上的传递。目前缺乏与胎盘药物转运体功能相关的数据，以指导临床实践选择和使用作为转运体底物的药物。这项拨款申请建议由三位经验丰富的联合首席调查员进行产科药理学研究，以提高我们指导妊娠期间药物使用的能力。提出了三个具体目标，以大大提高我们对胎盘在人类妊娠期的认识，并提高我们对主要药物转运体在调节胎儿药物暴露中的作用的理解。因此，我们选择了5种主要的转运蛋白进行研究：ABCB1基因编码的多药耐药蛋白或p -糖蛋白（P-gp）；ABCC3基因编码耐多药蛋白（MRP3）；ABCG2基因编码乳腺癌抵抗蛋白（BCRP）；SLC6A2基因编码去甲肾上腺素转运蛋白；SLC6A4基因编码血清素转运蛋白（SERT）。具体目的1将确定胎龄依赖性的蛋白质表达和功能活性的变化，每个转运体。特异性目标2将定义妊娠1、2、3个月暴露于底物的情况

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.