ALTERED HEPATIC DISPOSITION OF ANIONIC DRUGS-MECHANISMS

改变阴离子药物的肝脏处置机制

• 批准号: 8312797
• 负责人: KIM L.R. BROUWER
• 金额: $ 17.06万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-04-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312797
• 关键词: Abbreviations; Address; Affect; Attenuated; Bile Acids; Bile fluid; Biliary; Blood; Carrier Proteins; Cells; Chemicals; Clinical; Coupled; Data; Development; Disease; Drug Interactions; Drug Transport; Drug toxicity; Excretory function; Exposure to; Foundations; Funding; Genetic Predisposition to Disease; Glycocholate; Goals; Grant; HIV therapy; Hepatic; Hepatobiliary; Hepatocyte; Human; Image; In Vitro; Injury; Inorganic Sulfates; Intestines; Kinetics; Liver; Measures; Membrane; Modeling; Names; Outcome; Pharmaceutical Preparations; Pharmacotherapy; Play; Process; Proteins; Protocols documentation; RNA Interference; Rattus; Research; Ritonavir; Rodent; Role; Route; Secondary to; Staging; Sulindac; Sulindac Sulfide; System; Taurine Cholate; Techniques; Therapeutic; Toxic effect; Translations; Treatment Efficacy; Unspecified or Sulfate Ion Sulfates; Vesicle; Work; base; clinically relevant; clinically significant; drug development; drug efficacy; drug mechanism; healthy volunteer; hepatotoxin; improved; in vitro Model; in vivo; inhibitor/antagonist; knock-down; models and simulation; novel; pharmacokinetic model; prevent; programs; protein function; public health relevance; response; simulation; species difference; tool; toxicant interaction; transport inhibitor; troglitazone; uptake

DESCRIPTION (provided by applicant): The key role of transport proteins in the hepatic uptake and excretion of anionic drugs/metabolites is now widely recognized. Important progress during the current funding period has established that altered function of these transport proteins secondary to drug/toxicant interactions, disease states, or genetic predisposition may modulate systemic, intestinal (via bile) and/or hepatic exposure to drugs/metabolites and endogenous compounds, including bile acids. Such functional alterations have important therapeutic or toxicologic implications for some drugs. The long-term objective of this ongoing research program is to advance mechanistic understanding of how changes in transport function influence overall hepatobiliary disposition of anionic drugs/derived metabolites, and to develop tools to predict clinically-relevant outcomes of altered hepatic drug transport. The need for predictive probes/tools is imperative: research in the field of drug transport is still at an early stage, translation of this information to the clinical setting has been limited, and the potential for clinically- significant alterations in hepatic transport of drugs/metabolites is substantial. A multi-experimental approach incorporating state-of-the-art techniques including sandwich-cultured primary rat and human hepatocytes coupled with RNAi to selectively knock down transport proteins, in vitro expression systems, isolated perfused livers from wild-type and transport protein-deficient rodents, an in vivo human protocol using an MRP2 imaging agent as a phenotypic probe to assess hepatic drug transport interactions, and pharmacokinetic modeling/simulation will be employed to elucidate mechanisms and consequences of altered hepatic transport of model anionic drugs/metabolites. Proposed studies will address three key issues: 1) implications of the multiplicity of drug transport proteins on hepatobiliary drug/metabolite disposition in response to impaired transport function, 2) role of transport proteins in drug-induced liver injury, and 3) development of probes/tools to assess transport protein function. Elucidating mechanisms of altered hepatic drug transport, and identifying the functional consequences of those alterations, are prerequisite to exploiting these processes to achieve desirable clinical outcomes. PUBLIC HEALTH RELEVANCE: Transport proteins in the liver remove many drugs from the body, and may significantly influence drug efficacy or toxicity. This research will clarify how these transport proteins work in concert to control accumulation and excretion of drugs in the liver, and the impact of impaired transport function (e.g., by drugs or disease). An important goal is to develop tools to predict and assess altered drug transport in humans. Results of these studies will impact drug development, improve outcomes of drug therapy, and help prevent drug-induced liver injury.

描述(由申请人提供)：转运蛋白在肝脏对阴离子药物/代谢物的吸收和排泄中的关键作用现已得到广泛认可。本供资期间取得的重要进展表明，药物/毒物相互作用、疾病状态或遗传倾向引起的这些转运蛋白功能的改变可能会调节全身、肠道和/或肝脏对药物/代谢物和包括胆汁酸在内的内源性化合物的暴露。这种功能改变对某些药物具有重要的治疗或毒理学意义。这项正在进行的研究计划的长期目标是促进对运输功能的变化如何影响阴离子药物/衍生代谢物的整体肝胆处置的机械性理解，并开发工具来预测改变的肝脏药物运输的临床相关结果。对预测性探针/工具的需求是迫切的：药物转运领域的研究仍处于早期阶段，将这些信息转化到临床环境中的可能性有限，药物/代谢物肝脏转运发生临床显著变化的可能性很大。一种融合了先进技术的多实验方法，包括三明治培养的原代大鼠和人肝细胞与RNAi结合选择性地击倒转运蛋白，体外表达系统，从野生型和转运蛋白缺乏的啮齿类动物分离的灌流肝脏，使用MRP2显像剂作为表型探针来评估肝脏药物转运相互作用的体内人类方案，以及药代动力学建模/模拟将用于阐明模型阴离子药物/代谢物改变肝脏转运的机制和后果。建议的研究将涉及三个关键问题：1)药物转运蛋白的多样性对肝胆药物/代谢物转运功能受损的影响，2)转运蛋白在药物诱导的肝损伤中的作用，以及3)开发用于评估转运蛋白功能的探针/工具。阐明肝脏药物转运改变的机制，并确定这些改变的功能后果，是利用这些过程达到理想的临床结果的先决条件。 公共卫生相关性：肝脏中的转运蛋白将许多药物从体内清除出去，并可能显著影响药物的疗效或毒性。这项研究将阐明这些运输蛋白如何协同工作来控制药物在肝脏中的积累和排泄，以及运输功能受损(例如，药物或疾病)的影响。一个重要的目标是开发工具来预测和评估改变后的药物在人体内的传输。这些研究的结果将影响药物开发，改善药物治疗的结果，并有助于预防药物诱导的肝损伤。