ALTERED HEPATIC DISPOSITION OF ANIONIC DRUGS-MECHANISMS

改变阴离子药物的肝脏处置机制

• 批准号: 7251494
• 负责人: KIM L.R. BROUWER
• 金额: $ 30.88万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7251494
• 关键词: ABCC1 gene; Abbreviations; Acute; Address; Affect; Anions; Biliary; Carrier Proteins; Categories; Cells; Chemical Exposure; Clinical Protocols; Data; Disease; Drug Interactions; Drug Transport; Enzymes; Excretory function; Financial compensation; Funding; GF 120918; Genetic Predisposition to Disease; Genetic Variation; Hepatic; Hepatobiliary; Hepatocyte; Human; Impairment; In Vitro; Individual; Intestines; Kinetics; Liver; MK-571; Metabolism; Modeling; Nuclear Hormone Receptors; Oocytes; Outcome; Pharmaceutical Preparations; Phase; Play; Process; Protein Export Pathway; Protein Isoforms; Proteins; RNA; RNA Interference; Rattus; Research; Research Personnel; Ritonavir; Role; Secondary to; Small Interfering RNA; System; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Xenobiotics; Xenopus laevis; base; drug mechanism; human study; in vitro Model; in vivo; inhibitor/antagonist; intrahepatic; knock-down; lipoprotein lipase; mRNA Expression; novel; programs; research study; response; toxicant; transport inhibitor; uptake

DESCRIPTION (provided by applicant): Altered hepatic disposition of anionic drugs secondary to drug interactions, chemical exposure, disease states or genetic predisposition has important therapeutic implications. Systemic exposure, and therefore the magnitude and duration of pharmacologic response, may be affected substantially by changes in hepatic translocation of drugs. Likewise, perturbations in hepatic transport can influence systemic, intestinal and, perhaps most importantly, hepatic toxicity. The long-term objective of this ongoing research program is to develop a mechanistic understanding of how alterations in hepatic transport influence overall hepatobiliary disposition of anionic drugs and derived metabolites. A multiexperimental approach incorporating relevant in vitro expression systems (Sf9 cells, Xenopus laevis oocytes); a novel sandwich-cultured (SC) primary hepatocyte model that retains hepatic transport mechanisms, provides quantitative data on biliary and basolateral excretion, and is amenable to transporter knockdown by RNAi; isolated perfused livers using TR- rats, a model of Mrp2 deficiency; and an in vivo human study will be employed to elucidate mechanisms and consequences of altered hepatic transport of model anionic substrates. The hypothesis that multiple Mrp isoforms contribute to basolateral excretion of anionic drugs and metabolites from the liver will be tested, proteins that contribute significantly to this process will be identified, and kinetics of transport will be determined for model substrates. Purportedly "specific" inhibitors of hepatic canalicular transport may interact with basolateral transport proteins, resulting in a previously unrecognized category of drug-drug interactions. The ability of these inhibitors to modulate basolateral excretion, and the consequences of such modulation on hepatobiliary disposition, will be explored. The hypothesis that hepatic response mechanisms (basolateral exporters, other canalicular transporters, and hepatic Phase II enzymes) compensate for impaired Mrp2 function will be evaluated; the role of nuclear hormone receptors in these compensatory responses, and the kinetic consequences of such compensation, will be defined. Finally, the ability of human SC hepatocytes to predict hepatobiliary disposition of a model anion in humans will be assessed with a novel clinical protocol that allows quantitation of biliary excretion in healthy humans. Elucidating mechanisms of hepatic transport, and identifying functional consequences of alterations in these processes, is an important step in understanding the multiplicity of factors that determine systemic exposure (and ultimately biologic response) to xenobiotics, and is prerequisite to exploiting these processes to achieve desirable therapeutic outcomes.

描述（由申请人提供）：继发于药物相互作用、化学暴露、疾病状态或遗传倾向的阴离子药物的肝脏处置改变具有重要的治疗意义。全身暴露以及药理反应的强度和持续时间可能会受到药物肝转运变化的显着影响。同样，肝脏运输的扰动会影响全身毒性、肠道毒性，也许最重要的是影响肝脏毒性。这项正在进行的研究计划的长期目标是从机制上理解肝脏转运的改变如何影响阴离子药物和衍生代谢物的整体肝胆处置。结合相关体外表达系统（Sf9 细胞、非洲爪蟾卵母细胞）的多重实验方法；一种新型夹心培养（SC）原代肝细胞模型，保留肝脏转运机制，提供胆汁和基底外侧排泄的定量数据，并且适合通过 RNAi 敲低转运蛋白；使用 TR-大鼠（Mrp2 缺陷模型）分离灌注肝脏；将采用人体体内研究来阐明模型阴离子底物肝脏转运改变的机制和后果。我们将测试多种 Mrp 同种型有助于阴离子药物和代谢物从肝脏的基底外侧排泄的假设，将鉴定对这一过程有显着贡献的蛋白质，并确定模型底物的运输动力学。据称，肝小管转运的“特异性”抑制剂可能与基底外侧转运蛋白相互作用，导致以前未被认识的药物间相互作用类别。将探讨这些抑制剂调节基底外侧排泄的能力，以及这种调节对肝胆处置的影响。将评估肝脏反应机制（基底外侧输出蛋白、其他小管转运蛋白和肝 II 期酶）补偿受损的 Mrp2 功能的假设；核激素受体在这些补偿反应中的作用以及这种补偿的动力学后果将被定义。最后，将使用一种新的临床方案来评估人类 SC 肝细胞预测人类模型阴离子的肝胆处置的能力，该方案允许对健康人类的胆汁排泄进行定量。阐明肝脏转运机制，并确定这些过程改变的功能后果，是了解决定外源物质全身暴露（以及最终生物反应）的多种因素的重要一步，也是利用这些过程实现理想治疗结果的先决条件。