Mechanisms of Altered Hepatic Drug Metabolism and Transport in Pregnancy

摘要： 大约80%的孕妇在怀孕期间至少服用一种药物。然而，大多数药物 在妊娠期间开具的处方缺乏针对该未充分研究的弱势人群的剂量信息。这 紧急的、未满足的公共卫生需求导致标签外处方、试错药物剂量、治疗失败， 和毒性作用。缺乏更精确的剂量建议，很大程度上是因为 对孕妇肝脏药物处置（代谢和转运）的改变了解甚少。药物 肝脏中的代谢酶（DME）和转运蛋白对于许多药物的清除和作用是不可或缺的。 怀孕期间使用的药物。因此，彻底的机械理解的关键因素，改变 妊娠期间肝脏药物代谢和转运对于更精确地预测体内变化至关重要 在清除中，优化药物选择和剂量，并改善母体和胎儿结局。我们的中央 假设是妊娠引起的激素变化显著影响母体药物清除， 通过改变肝脏中关键DME和药物转运蛋白的表达和功能来减少暴露。整体 本项目的目的是系统地阐明妊娠激素如何以及在何种程度上改变肝脏的功能， 药物代谢和转运，以及产科患者中使用的临床相关药物的肝脏清除率。 我们将通过研究妊娠激素对肝脏key表达的影响来验证我们的假设。 I期和II期DME和药物转运蛋白，以及所用已确立和新出现药物的肝脏分布 治疗妊娠期高血压疾病（硝苯地平、拉贝洛尔、普伐他汀）和阿片类药物使用障碍， 妊娠（丁丙诺啡），表现出互补的肝脏清除机制。这些影响将是 与关键清除途径的原型探针基质相比， 额外的药物。以下具体目标将通过完成机制驱动的 在体外培养的人肝细胞和人源化小鼠中的实验：（AIM 1）阐明 妊娠激素对关键I期和II期DME的肝脏表达以及药物摄取和外排的影响 转运蛋白;（目的2）确定妊娠激素对临床肝代谢的影响， 通过关键I期（CYP 3A 4）和II期（UGT 1A 1）DME评估相关药物和探针底物;（AIM 3）评估 妊娠激素对关键肝摄取和外排转运蛋白功能的影响，以及妊娠激素对肝摄取和外排转运蛋白功能的影响。 临床相关药物和探针底物的肝胆处置。该项目将提供基本的 关于妊娠激素改变肝脏药物代谢的机制和程度的新知识， 药物在肝脏的转运和清除，建立一个阐明肝脏药物代谢的实验平台， 妊娠期间的处置变化，可系统地应用于肝脏清除的其他药物; 告知临床药代动力学研究和建模分析的设计、分析和解释， 孕妇;并最终改善产科患者的药物剂量、安全性和有效性。

ABSTRACT: Approximately 80% of pregnant women take at least one medication during pregnancy. However, most drugs prescribed during pregnancy lack dosing information specific to this understudied vulnerable population. This urgent, unmet public health need results in off-label prescribing, trial-and-error drug dosing, therapeutic failures, and toxic effects. More precise dosing recommendations are lacking in large part because the key factors that alter hepatic drug disposition (metabolism and transport) in pregnant women are poorly understood. Drug metabolizing enzymes (DMEs) and transporters in the liver are integral to the clearance and effects of numerous drugs used during pregnancy. Consequently, a thorough mechanistic understanding of the key factors that alter hepatic drug metabolism and transport during pregnancy is essential to more precisely predict in vivo changes in clearance, optimize drug selection and dosing, and improve maternal and fetal outcomes. Our central hypothesis is that pregnancy-induced hormonal changes significantly affect maternal drug clearance and exposure by altering the expression and function of key DMEs and drug transporters in the liver. The overall objective of this project is to systematically elucidate how, and to what extent, pregnancy hormones alter hepatic drug metabolism and transport, and the hepatic clearance of clinically relevant drugs used in obstetric patients. We will test our hypothesis by investigating the effects of pregnancy hormones on the hepatic expression of key phase I and II DMEs and drug transporters, and the hepatic disposition of established and emerging drugs used to treat hypertensive disorders of pregnancy (nifedipine, labetalol, pravastatin) and opioid use disorder in pregnancy (buprenorphine) that exhibit complementary hepatic clearance mechanisms. These effects will be compared to prototypical probe substrates of key clearance pathways to enable extrapolation of results to additional drugs. The following specific aims will be accomplished through completion of mechanism-driven experiments in sandwich-cultured human hepatocytes and humanized mice: (AIM 1) elucidate the effects of pregnancy hormones on the hepatic expression of key phase I and phase II DMEs, and drug uptake and efflux transport proteins; (AIM 2) define the impact of pregnancy hormones on the hepatic metabolism of clinically relevant drugs and probe substrates by key phase I (CYP3A4) and phase II (UGT1A1) DMEs; (AIM 3) evaluate the impact of pregnancy hormones on the function of key hepatic uptake and efflux transport proteins, and the hepatobiliary disposition of clinically relevant drugs and probe substrates. This project will provide fundamental new knowledge on the mechanisms and extent to which pregnancy hormones alter hepatic drug metabolism and transport, and the hepatic clearance of drugs; establish an experimental platform that elucidates hepatic drug disposition changes during pregnancy and can be applied systematically to additional drugs cleared by the liver; inform the design, analysis and interpretation of clinical pharmacokinetic studies and modeling analyses in pregnant women; and, ultimately improve medication dosing, safety and effectiveness in obstetric patients.