ALTERED HEPATIC DISPOSITION OF ANIONIC DRUGS-MECHANISMS

继发于药物相互作用、化学品暴露、疾病状态的阴离子药物的肝脏处置改变 或遗传易感性具有重要的治疗意义。全身暴露，因此 药理学反应的程度和持续时间可能受到肝脏 毒品的转移。同样，肝脏转运的扰动可以影响全身、脑内和脑内， 也许最重要的是肝毒性。这项正在进行的研究计划的长期目标是 了解肝脏转运的改变如何影响整体肝胆 阴离子药物和衍生代谢物的处置。一种多实验方法， 体外表达系统（Sf9细胞，非洲爪蟾卵母细胞）;一种新的体外培养（SC）原代 保留肝脏转运机制的肝细胞模型，提供了胆汁和 基底外侧排泄，并且易于通过RNAi敲低转运蛋白;使用TR " 大鼠，Mrp2缺陷模型;和体内人体研究将用于阐明机制， 模型阴离子底物的肝脏转运改变的后果。假设多个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， 将鉴定出对这一过程有重要贡献的蛋白质，并将研究运输动力学。 确定模型基板。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，导致以前未认识到的药物-药物 交互.这些抑制剂调节基底外侧排泄的能力，以及这种调节的后果， 调节肝胆处置，将进行探讨。假设肝脏反应机制 （基底外侧输出者，其他小管转运蛋白和肝脏II相酶）补偿受损的 将评估mrp2功能;核激素受体在这些代偿反应中的作用，以及 将定义这种补偿的动力学结果。最后，人SC肝细胞的能力 预测模型阴离子在人体中的肝胆处置将采用新的临床方案进行评估 可以定量健康人的胆汁排泄。阐明肝脏转运机制， 并确定这些过程中改变的功能后果，是重要的一步， 了解决定全身暴露（以及最终生物学反应）的多种因素 外源性物质，并且是利用这些过程以实现期望的治疗结果的先决条件。

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, intestinaland, 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 usingTR" 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.