Mechanisms of Drug Disposition During Pregnancy

描述(申请人提供)：怀孕期间使用非法药物是孕产妇和胎儿发病率的主要风险因素。此外，合法药物通常用于孕妇，因此也就是她们的胎儿，而没有关于这些药物在这些脆弱人群中的药代动力学的必要数据。该方案的总体目标是在怀孕期间使用有效的药物(合法药物)和更安全的药物(合法和非法药物)。我们将通过检验以下最重要和统一的中心假设来实现这一目标：妊娠期间肝脏细胞色素P450酶和胎盘药物转运蛋白的表达和活性受妊娠相关激素和/或生长因子以及药物和外源物质的影响。阐明这些机制并量化妊娠引起的这些细胞色素P450和转运蛋白活性的变化，将使PBPK能够预测怀孕期间母婴暴露于药物的变化。我们将研究的P450酶和转运体是那些可能在数量上对非法和合法药物在肝脏或胎盘中的新陈代谢和运输最重要的酶和转运体，即CYP3A(项目1)、CYP2B6和CYP2D6(项目2)、P-gp和BCRP(项目3)，以及OCTS、NET和SERT(项目4)。已知怀孕会诱导肝脏细胞色素P3A和细胞色素P450 2 D6的表达和活性，因此可能会降低母亲对药物的暴露，并可能降低其疗效。在胎盘中，P-gp和BCRP参与药物从胎儿隔室到母体循环的外流，从而保护胎儿免受药物的不良影响，而0CT3、NET和/或SERT的功能允许潜在的有毒药物进入胎儿循环。THI POI使用协作、协同、多学科和系统药理学的方法来检验上述假设。拟议的研究结果将使我们能够预测孕妇和胎儿对合法和非法药物的暴露如何受到怀孕和胎龄的影响，并将揭示有趣的和潜在的新机制，对所研究的细胞色素P450和转运蛋白进行生理调节。

DESCRIPTION (provided by applicant): Illicit drug use during pregnancy is a major risk factor for maternal and fetal morbidity. In addition, licit drugs are routinely administered to pregnant women, and therefore their fetuses, without the necessary data about the pharmacokinetics of these drugs in these vulnerable populations. The overall goal of this POI is to make use of drugs during pregnancy efficacious (licit drugs) and safer (licit and illicit drugs). We will achieve thi goal by testing the following overarching and unifying central hypothesis: Expression and activity of hepatic cytochrome P450 enzymes and placental drug transporters during pregnancy are regulated by pregnancy- related hormones and/or growth factors and by exposure to drugs and xenobiotics. Elucidating these mechanisms and quantifying the pregnancy-induced changes in these CYP and transporter activities will allow PBPK prediction of changes in maternal-fetal exposure to drugs througout pregnancy. The P450 enzymes and transporters we will study are those likely to be quantitatively most important for metabolism and transport of both illicit and licit drugs in the liver or the placenta, namely CYP3A (Project 1), CYP2B6 and CYP2D6 (Project 2), P-gp and BCRP (Project 3), and OCTS, NET, and SERT (Project 4). Pregnancy is known to induce expression and activity of hepatic CYP3A and CYP2D6, thus possibly lowering maternal exposure to drugs and potentially decreasing their efficacy. In the placenta, P-gp and BCRP participate in the efflux of drugs from the fetal compartment to the maternal circulation, thus protecting the fetus from adverse effects of drugs, while 0CT3, NET and/or SERT function to allow the entry of potentially toxic drugs into the fetal circulation. Thi POI uses a collaborative, synergistic, multidisciplinary and systems pharmacology approach to test the above-stated hypothesis. Results obtained from the proposed studies will allow us to predict how maternal and fetal exposure to licit and illicit drugs is affected by pregnancy and by gestational age and will reveal interesting and potentially novel mechanisms on physiological regulation of CYPs and transporters studied.