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.

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