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: 9903951
• 负责人: CRAIG R LEE
• 金额: $ 43.66万
• 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/9903951
• 关键词: 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; Knowledge; Labetalol; Liver; Mediating; Metabolism; Mus; Nifedipine; Outcome; P-Glycoprotein; 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％的孕妇在怀孕期间服用至少一种药物。但是，大多数药物 怀孕期间的规定缺乏针对该研究不足的脆弱人群的剂量信息。这 紧急，未满足的公共卫生需求会导致标签开处方，试用药物给药，治疗失败， 和有毒作用。在很大程度上缺乏更精确的给药建议，因为 对孕妇的改变肝药物处置（代谢和运输）的理解很少。药品 肝脏中的代谢酶（DME）和转运蛋白是众多清除和影响不可或缺的一部分 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理解 肝药物代谢和怀孕期间的运输对于更精确预测体内变化至关重要 在清除时，优化药物选择和剂量，并改善产妇和胎儿结果。我们的中心 假设是妊娠引起的激素变化显着影响母体药物清除率和 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。总体 该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 药物代谢和运输，以及用于产科患者使用的临床相关药物的肝清除率。 我们将通过研究怀孕激素对肝的肝表达的影响来检验我们的假设 第一阶段和II DME和药物转运蛋白，以及所使用的已建立药物的肝脏处置 治疗怀孕的高血压疾病（硝苯地平，Labetalol，pravastatin）和阿片类药物使用障碍 妊娠（丁丙诺啡）具有互补的肝清除机制。这些影响将是 与关键清除途径的原型探针基板相比 其他药物。通过完成机构驱动的以下特定目标将实现 三明治培养的人肝细胞和人源化小鼠的实验：（目标1）阐明 关键I期和II期DME的肝表达上的怀孕激素以及药物吸收和外排 转运蛋白； （AIM 2）定义妊娠激素对临床上肝代谢的影响 相关药物和探针底物通过关键I期（CYP3A4）和II期（UGT1A1）DMES； （目标3）评估 妊娠激素对关键肝摄取和外排运输蛋白功能的影响，以及 肝合临床相关的药物和探针底物的肝屈服。该项目将提供基本 关于妊娠激素改变肝药物代谢的机制和程度的新知识 运输和肝清除药物；建立一个阐明肝药物的实验平台 怀孕期间的处置变化，可以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的设计，分析和解释以及建模分析 孕妇；并且，最终改善了产科患者的药物剂量，安全性和有效性。