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 在怀孕期间开出的处方缺乏针对这一研究不足的脆弱人群的剂量信息。这 紧急的、未得到满足的公共卫生需求导致标签外的处方、反复尝试的药物剂量、治疗失败， 以及毒害作用。缺乏更准确的剂量建议在很大程度上是因为 对孕妇肝脏药物处置(代谢和转运)的改变知之甚少。药效 肝脏中的代谢酶(DME)和转运蛋白是清除和影响许多 怀孕期间使用的药物。因此，对改变的关键因素有彻底的机械性理解 妊娠期间肝脏药物代谢和转运对于更准确地预测体内变化是必不可少的 在清除方面，优化药物选择和剂量，改善母婴结局。我们的中央 假说是妊娠引起的荷尔蒙变化显著影响母亲的药物清除和 通过改变肝脏中关键的DME和药物转运蛋白的表达和功能而暴露。整体而言 该项目的目标是系统地阐明妊娠激素如何以及在多大程度上改变肝脏。 药物代谢和转运，以及产科患者使用的临床相关药物的肝清除。 我们将通过研究怀孕激素对KEY基因肝脏表达的影响来检验我们的假设 第一阶段和第二阶段DMES和药物转运体，以及已使用和正在使用的药物的肝脏处置 治疗妊娠高血压疾病(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 与关键间隙路径的原型探针底物相比，能够将结果外推到 额外的药物。通过完成机制驱动，实现以下具体目标 在三明治培养的人肝细胞和人源化小鼠上的实验：(目的1)阐明三七总皂甙的作用 妊娠激素对肝脏关键的I期和II期Dme表达及药物摄取和外排的影响 转运蛋白；(目的2)明确妊娠激素对临床上肝脏代谢的影响。 相关药物和探针底物通过关键一期(CYP3A4)和二期(UGT1A1)DMES；(AIM 3)评价 妊娠激素对关键的肝脏摄取和外排运输蛋白功能的影响 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 妊娠激素改变肝脏药物代谢的机制和程度的新认识 药物的转运和肝脏清除；建立阐明肝脏药物的实验平台 性情在怀孕期间发生变化，可系统地应用于经肝脏清除的其他药物； 为临床药代动力学研究和模型分析的设计、分析和解释提供信息 并最终提高产科患者的用药剂量、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.