ALTERED HEPATIC DISPOSITION OF ANIONIC DRUGS-MECHANISMS

性状（由申请人提供）：转运蛋白在阴离子药物/代谢物的肝脏摄取和排泄中的关键作用现已得到广泛认可。本资助期内的重要进展已经确定，继发于药物/毒物相互作用、疾病状态或遗传易感性的这些转运蛋白的功能改变可能调节药物/代谢物和内源性化合物（包括胆汁酸）的全身、肠道（通过胆汁）和/或肝脏暴露。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转运功能变化如何影响阴离子药物/衍生代谢物的总体肝胆处置的机制理解，并开发预测肝脏药物转运改变的临床相关结局的工具。对预测探针/工具的需求是必要的：药物转运领域的研究仍处于早期阶段，将该信息转化为临床环境是有限的，并且药物/代谢物的肝脏转运的临床显著改变的潜力是巨大的。多实验方法结合了最先进的技术，包括体外培养的原代大鼠和人肝细胞与RNAi偶联以选择性敲低转运蛋白，体外表达系统，来自野生型和转运蛋白缺陷型啮齿动物的分离灌注肝脏，使用MRP 2成像剂作为表型探针评估肝脏药物转运相互作用的体内人方案，和药代动力学建模/模拟将用于阐明模型阴离子药物/代谢物的肝脏转运改变的机制和后果。拟定的研究将解决三个关键问题：1）药物转运蛋白的多样性对肝胆药物/代谢物处置的影响，以响应受损的转运功能，2）转运蛋白在药物诱导的肝损伤中的作用，和3）开发探针/工具来评估转运蛋白的功能。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实现理想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，并可能显著影响药物疗效或毒性。这项研究将阐明这些转运蛋白如何协同工作以控制药物在肝脏中的积累和排泄，以及转运功能受损的影响（例如，药物或疾病）。一个重要的目标是开发工具来预测和评估人类药物转运的改变。这些研究的结果将影响药物开发，改善药物治疗的结果，并有助于预防药物性肝损伤。

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.