ALTERED HEPATIC DISPOSITION OF ANIONIC DRUGS-MECHANISMS

继发于药物相互作用、化学暴露、疾病状态或遗传变异的阴离子药物的肝脏处置改变具有重要的治疗意义。 药物的肝移位变化可能会显著改变全身暴露量和药理活性持续时间。 同样，改变的肝脏转运可影响全身、肝脏或肠道毒性。 本研究项目的长期目标仍然是从机制上了解肝脏转运的扰动如何影响阴离子药物和衍生代谢物的总体肝胆处置。 一个多实验的方法，利用在体内，离体灌注大鼠肝脏，并在体外细胞系统将被用来阐明肝脏有机阴离子转运系统的功能改变的机制。 将检验肝小管（Mrp 2）和基底外侧（Mrp 3）转运蛋白以协调方式调节胆汁排泄、肝内浓度和阴离子底物全身暴露的假设。 将评价体外模型系统的效用，以探索肝胆转运改变的机制，包括转运蛋白调节和转运的基本方面，并预测功能后果。 该模型系统代表了一个令人兴奋的工具，用于研究肝胆药物处置，因为它保持肝细胞极性和胆小管功能，允许直接进入肝细胞和邻近的胆管室，并尽量减少使用实验动物。 将这种体外方法扩展到人肝细胞可能提供一种新的方法来研究人肝胆系统中的肝脏转运机制和药物转运相互作用。 将进行一项初步研究，以验证定量人体胆汁排泄的方法，从而评价体外/体内相关性。 阐明肝脏有机阴离子转运的机制，以及异生物质相互作用或生理变化如何改变这些过程的知识，对于理解肝脏如何处理内源性和外源性化合物至关重要。 这些信息将有助于对肝脏转运改变后的肝脏异生物质/代谢物处置进行先验预测，并且是利用肝脏转运过程实现理想治疗终点的先决条件。 这项工作的优点是实现时，一个考虑的数量进行肝脏消除的外源性物质，并改变这些代理人的肝脏运输的潜力。

Altered hepatic disposition of anionic drugs secondary to drug interactions, chemical exposure, disease states or genetic variations has important therapeutic implications. Systemic exposure and duration of pharmacologic activity may be altered substantially by changes in hepatic translocation of drugs. Likewise, altered hepatic transport can influence systemic, hepatic, or intestinal toxicity. The long-term objective of this research program continues to be the development of a mechanistic understanding of how perturbations in hepatic transport influence overall hepatobiliary disposition of anionic drugs and derived metabolites. A multiexperimental approach utilizing in vivo, isolated perfused rat liver, and in vitro cellular systems will be employed to elucidate mechanisms of altered function of hepatic organic anion transport systems. The hypothesis that hepatic canalicular (Mrp2) and basolateral (Mrp3) transporters function in a coordinate fashion to modulate biliary excretion, intrahepatic concentrations and systemic exposure of anionic substrates will be tested. The utility of an in vitro model system to explore mechanisms of altered hepatobiliary transport, including fundamental aspects of transporter regulation and trafficking, and to predict functional consequences, will be evaluated. This model system represents an exciting tool for studying hepatobiliary drug disposition as it maintains hepatocyte polarity and bile canalicular function, allows direct access to the hepatocyte and adjacent biliary compartment, and minimized the use of experimental animals. Extension of this in vitro methodology to human hepatocytes may provide a novel approach to examine hepatic transport mechanisms and drug transport interaction in the human hepatobiliary system. A pilot study to validate a method of quantify biliary excretion in humans will be performed to evaluate in vitro/in vivo correlations. Elucidation of the mechanisms of hepatic organic anion transport, and knowledge of how xenobiotic interactions or physiologic variations alter these processes, is fundamental to understanding how the liver disposes of endogenous and exogenous compounds. This information will facilitate a priori predictions of hepatic xenobiotic/metabolite disposition in response to altered hepatic transport, and is prerequisite to exploiting hepatic transport processes to achieve desirable therapeutic endpoints. The merit of this work is realized when one considers the number of xenobiotics that undergo hepatic elimination, and the potential for alterations in hepatic transport of these agents.