Mechanisms of Drug Disposition During Pregnancy

描述（由申请人提供）：妊娠期间使用非法药物是孕产妇和胎儿发病的主要风险因素。此外，合法药物通常用于孕妇，因此也用于孕妇的胎儿，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POI的总体目标是使怀孕期间使用药物有效（合法药物）和更安全（合法和非法药物）。我们将通过测试以下总体和统一的中心假设来实现这一目标：妊娠期间肝细胞色素P450酶和胎盘药物转运蛋白的表达和活性受到妊娠相关激素和/或生长因子以及药物和外源性物质暴露的调节。阐明这些机制和定量妊娠诱导的这些转运蛋白和转运蛋白活性的变化将允许PBPK预测母体-胎儿暴露于药物的变化。我们将研究的P450酶和转运蛋白可能是对肝脏或胎盘中非法和合法药物的代谢和转运在数量上最重要的酶和转运蛋白，即CYP 3A（项目1）、CYP 2B 6和CYP 2D 6（项目2）、P-gp和BCRP（项目3）以及OCTS、NET和SERT（项目4）。已知妊娠可诱导肝脏CYP 3A和CYP 2D 6的表达和活性，因此可能降低母体药物暴露并可能降低其疗效。在胎盘中，P-gp和BCRP参与药物从胎儿室流出至母体循环，从而保护胎儿免受药物的不良影响，而OCT 3、NET和/或SERT的功能是允许潜在毒性药物进入胎儿循环。Thi POI使用协作，协同，多学科和系统药理学方法来测试上述假设。从拟议的研究中获得的结果将使我们能够预测母体和胎儿暴露于合法和非法药物是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的CYP和转运蛋白的生理调节研究。

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.