ALTERED HEPATIC DISPOSITION OF ANIONIC DRUGS-MECHANISMS

药物相互作用、化学物质暴露、疾病状态或遗传变异引起的阴离子药物肝脏处置的改变具有重要的治疗意义。全身性暴露和药理活性持续时间可能会因药物肝脏转运的改变而发生实质性改变。同样，肝脏转运改变也会影响全身、肝脏或肠道毒性。这项研究计划的长期目标仍然是发展对肝脏转运的扰动如何影响阴离子药物和衍生代谢物的整体肝胆处置的机械性理解。利用体内、隔离灌流的大鼠肝脏和体外细胞系统的多实验方法将被用来阐明肝脏有机阴离子转运系统功能改变的机制。肝小管(Mrp2)和基底外侧(Mrp3)转运体以协调方式调节胆汁排泄、肝内浓度和全身阴离子底物暴露的假说将得到验证。将评估体外模型系统在探索改变的肝胆运输机制方面的作用，包括转运体调节和运输的基本方面，并预测功能后果。这一模型系统是研究肝胆药物处置的一个令人兴奋的工具，因为它维持了肝细胞的极性和胆小管功能，允许直接进入肝细胞和邻近的胆管室，并最大限度地减少了实验动物的使用。将这一体外方法学推广到人肝细胞，可能为研究人肝胆系统的肝转运机制和药物转运相互作用提供一种新的途径。将进行一项初步研究，以验证一种量化人类胆汁排泄量的方法，以评估体外/体内相关性。阐明肝脏有机阴离子转运的机制，以及了解外来生物的相互作用或生理变化如何改变这些过程，是了解肝脏如何处置内源性和外源性化合物的基础。这些信息将有助于对肝脏异物/代谢物处置的先验预测，以响应肝脏运输的改变，并是利用肝脏运输过程达到理想的治疗终点的先决条件。当人们考虑到经历肝脏消除的外源物质的数量以及这些物质在肝脏转运中发生变化的可能性时，这项工作的好处就意识到了。

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.