Mechanisms of Altered Hepatic Drug Metabolism and Transport in Pregnancy

妊娠期肝脏药物代谢和转运改变的机制

• 批准号: 10380640
• 负责人: CRAIG R LEE
• 金额: $ 39.36万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380640
• 关键词: ABCB1 gene; Address; Affect; Biliary; Biological Markers; Buprenorphine; CYP3A4 gene; Carrier Proteins; Clinical; Cytochrome P450; Discipline of obstetrics; Dose; Drug Exposure; Drug Kinetics; Drug Prescriptions; Drug Transport; Drug usage; Effectiveness; Enzymes; Excretory function; Exhibits; Failure; Glucuronides; Glucuronosyltransferase; Gonadal Steroid Hormones; Hepatic; Hepatobiliary; Hepatocyte; Hormonal Change; Hormones; Human; Hypertension; Knowledge; Labetalol; Liver; Mediating; Metabolism; Mus; Nifedipine; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Physiological; Pravastatin; Pregnancy; Pregnant Women; Prevalence; Proteomics; Public Health; Recombinants; Recommendation; Research Project Grants; Safety; Study models; System; Testing; Therapeutic; Toxic effect; Treatment Failure; UDP-Glucuronosyltransferase 1A1; UGT1A1 gene; Vulnerable Populations; base; clinically relevant; design; dose information; drug clearance; drug disposition; drug metabolism; exosome; experimental study; fetal; humanized mouse; improved; in vivo; interpatient variability; liver metabolism; metabolic abnormality assessment; off-label use; opioid use disorder; pharmacokinetic model; pregnancy disorder; pregnant; protein expression; response; uptake

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.

抽象的： 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 怀孕期间的处方缺乏针对这一未充分研究的弱势群体的具体剂量信息。这 紧迫的、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关键因素 对于孕妇肝脏药物处置（代谢和转运）的改变知之甚少。药品 肝脏中的代谢酶 (DME) 和转运蛋白对于多种物质的清除和作用至关重要。 怀孕期间使用的药物。因此，对改变的关键因素有一个彻底的机械理解 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至关重要 在清除方面，优化药物选择和剂量，并改善母婴结局。我们的中央 假设是妊娠引起的荷尔蒙变化显着影响母体药物清除率 通过改变肝脏中关键 DME 和药物转运蛋白的表达和功能来暴露。整体 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脏清除率。 我们将通过研究妊娠激素对肝脏关键蛋白表达的影响来检验我们的假设。 I 期和 II 期 DME 和药物转运体，以及已使用的现有药物和新兴药物的肝脏处置 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底物进行比较，以便将结果外推到 额外的药物。通过完善机制驱动，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中进行的实验：（目的 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流出的影响 转运蛋白； (AIM 2) 临床上定义妊娠激素对肝脏代谢的影响 关键 I 期 (CYP3A4) 和 II 期 (UGT1A1) DME 的相关药物和探针底物； (目标 3) 评估 妊娠激素对关键肝脏摄取和流出转运蛋白功能的影响，以及 临床相关药物和探针底物的肝胆处置。该项目将提供基础 关于妊娠激素改变肝脏药物代谢的机制和程度的新知识 药物的运输和肝脏清除；建立肝药阐明实验平台 怀孕期间的处置发生变化，可以系统地应用由肝脏清除的其他药物； 为临床药代动力学研究和建模分析的设计、分析和解释提供信息 孕妇；并最终改善产科患者的药物剂量、安全性和有效性。