ALTERED HEPATIC DISPOSITION OF ANIONIC DRUGS-MECHANISMS

改变阴离子药物的肝脏处置机制

• 批准号: 6635990
• 负责人: KIM L.R. BROUWER
• 金额: $ 28.99万
• 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 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6635990
• 关键词: acetaminophen; anions; blood chemistry; clinical research; drug interactions; drug metabolism; fluoresceins; fluoroscopy; glucuronides; human subject; ion transport; laboratory rat; liver cells; liver imaging /visualization /scanning; liver metabolism; liver pharmacology; microtubules; pharmacokinetics; phenobarbital; phosphatidylinositol 3 kinase; probenecid; protein kinase A; radiography; toxin metabolism; transport inhibitor

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.

药物相互作用、化学暴露、疾病状态或遗传变异继发的阴离子药物的肝脏处置改变具有重要的治疗意义。 药物肝转运的变化可能会显着改变全身暴露和药理活性持续时间。 同样，肝脏转运的改变也会影响全身、肝脏或肠道毒性。 该研究计划的长期目标仍然是对肝脏运输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产生机械性的理解。 利用体内、分离的灌注大鼠肝脏和体外细胞系统的多重实验方法将用于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) 转运蛋白以协调方式发挥作用以调节胆汁排泄、肝内浓度和阴离子底物的全身暴露的假设将得到测试。 将评估体外模型系统在探索改变肝胆转运的机制（包括转运蛋白调节和运输的基本方面）以及预测功能后果方面的效用。 该模型系统是研究肝胆药物配置的一个令人兴奋的工具，因为它保持肝细胞极性和胆管功能，允许直接进入肝细胞和邻近的胆管室，并最大限度地减少实验动物的使用。 将这种体外方法扩展到人类肝细胞可能会提供一种新的方法来检查人类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，以验证量化人类胆汁排泄的方法，以评估体外/体内相关性。 阐明肝脏有机阴离子转运的机制，以及了解外源性相互作用或生理变化如何改变这些过程，对于理解肝脏如何处理内源性和外源性化合物至关重要。 该信息将有助于对肝脏异生素/代谢物处置的先验预测，以响应肝脏转运的改变，并且是利用肝脏转运过程实现所需治疗终点的先决条件。 当人们考虑到经过肝脏消除的外源性物质的数量以及这些药物肝脏转运发生改变的潜力时，我们就意识到了这项工作的优点。