Mechanisms of Altered Hepatic Transport: Impact on Drug Therapy

肝脏转运改变的机制：对药物治疗的影响

• 批准号: 10598589
• 负责人: KIM L.R. BROUWER
• 金额: $ 60.78万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-05 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598589
• 关键词: 3-Dimensional; Address; Bile Acids; Biliary; Biological Markers; Carrier Proteins; Data; Development; Drug Interactions; Drug Kinetics; Drug Transport; Excretory function; Goals; Grant; Hepatic; Hepatocyte; Homeostasis; Human; In Vitro; Laboratories; Liver; Mediating; Methods; Modeling; National Institute of General Medical Sciences; Organoids; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Phosphorylation Site; Physiological; Play; Regulation; Research; Role; Safety; Science; System; Toxic effect; bile acid transporter; cholangiocyte; clinical predictors; defined contribution; drug disposition; drug efficacy; exosome; improved; in silico; in vivo; inhibitor; innovation; inter-individual variation; novel; novel strategies; predictive tools; programs; response; solute; therapy outcome; tool; trafficking

Transport proteins in the liver play a critical role in drug disposition and interindividual variability in medication response. Many intrinsic and extrinsic factors influence hepatic transporter function. Understanding these factors, and the mechanisms involved, is fundamental to improving the safety and efficacy of drug therapy. The overall goals of my research program are to elucidate mechanisms of hepatic transport and further develop strategies to assess and predict the impact of altered hepatic transporter function on drug disposition to improve therapeutic outcomes. My laboratory has pioneered the development of in vitro tools to quantify hepatic drug disposition and biliary excretion, devised novel strategies to address key scientific questions regarding hepatic drug transport, and investigated the interplay between bile acids (BAs) and hepatic efflux transporters. Supported by an NIGMS MIRA grant, we established the importance of the human organic solute transporter alpha/beta (OSTα/β) in maintaining hepatic BA homeostasis and developed new in vitro methods to investigate drug substrates and inhibitors of OSTα/β, uncovered novel regulatory mechanisms of hepatic transporters, and advanced transporter science by developing in silico models to predict the clinical impact of altered drug transport. However, many important questions remain unanswered. What alternative mechanisms of transporter regulation impact hepatic drug disposition? We will continue to uncover novel mechanisms of transporter regulation. Using our optimized in vitro system, we will identify drugs that alter cellular trafficking of transporters, elucidate transporter-mediated drug interactions (tDIs) involving modulation of phosphorylation sites in transporters, and evaluate the impact of these changes on hepatic transporter function. Which emerging in vitro liver systems can advance our understanding of hepatic transporter mechanisms? We will assess hepatic transport in 3D liver organoid and liver-on-a-chip systems, optimize transporter expression, localization, and function in these systems, and develop strategies to use these systems to inform in silico models to improve predictions of drug disposition and tDIs. What role do cholangiocyte transporters play in hepatic drug disposition and tDIs? Cholangiocytes express hepatic drug and BA transporters, and are critical in hepatic BA regulation. We will define the contribution of cholangiocyte transporters and the hepatocyte-cholangiocyte interplay in drug disposition and tDIs. Incorporation of cholangiocytes into in vitro liver systems may further enhance predictions. Can novel tools improve transporter function assessment and predict hepatic drug disposition in vivo? We will continue mechanistic studies to elucidate factors that impact the use of endogenous biomarkers for tDI studies, and explore hepatocyte-derived exosomes as a noninvasive method to quantify hepatic transporter phenotype. Development of novel mechanistic, physiologically-based pharmacokinetic, and quantitative systems pharmacology models informed by in vitro data will more accurately predict the impact of altered hepatic transport on drug disposition. This information is critical to optimize therapeutic outcomes.

肝脏中的转运蛋白在药物处置和药物治疗的个体间差异中起着关键作用 反应许多内在和外在因素影响肝转运蛋白功能。了解这些 这些因素以及相关机制的研究对于提高药物治疗的安全性和有效性至关重要。的 我的研究计划的总体目标是阐明肝脏转运的机制，并进一步发展 评估和预测肝转运蛋白功能改变对药物处置的影响的策略， 治疗结果。我的实验室率先开发了体外工具来量化肝脏药物 处置和胆汁排泄，设计了新的策略，以解决有关肝脏的关键科学问题， 药物转运，并研究胆汁酸（BA）和肝外排转运蛋白之间的相互作用。支持 通过NIGMS MIRA的资助，我们确定了人类有机溶质转运蛋白α/β的重要性， (OSTα/β）维持肝脏BA稳态的作用，并发展了新的体外研究药物 OSTα/β的底物和抑制剂，揭示了肝脏转运蛋白的新调控机制， 通过开发计算机模型来预测改变药物的临床影响， 运输然而，许多重要问题仍然没有答案。有哪些替代机制 转运蛋白调节影响肝脏药物处置？我们将继续发现新的机制， 运输管制。使用我们优化的体外系统，我们将确定改变细胞运输的药物， 转运蛋白，阐明涉及磷酸化调节的转运蛋白介导的药物相互作用（tDI） 转运蛋白的位点，并评估这些变化对肝转运蛋白功能的影响。哪些新兴 体外肝脏系统可以促进我们对肝脏转运机制的理解？我们将评估 在3D肝类器官和肝芯片系统中肝转运，优化转运蛋白表达、定位 并在这些系统中发挥作用，并制定策略，使用这些系统来通知计算机模型，以改善 药物处置和tDI的预测。胆管细胞转运蛋白在肝脏药物治疗中起什么作用 处置和TDI？胆管细胞表达肝脏药物和BA转运体，在肝脏BA中起关键作用 调控我们将明确胆管细胞转运蛋白和肝细胞-胆管细胞 药物处置和tDI的相互作用。将胆管细胞并入体外肝脏系统可能进一步 加强预测。新的工具可以改善转运蛋白功能评估并预测肝脏药物 体内处置？我们将继续进行机制研究，以阐明影响内源性药物使用的因素。 用于tDI研究的生物标志物，并探索肝细胞来源的外泌体作为一种非侵入性方法， 肝转运蛋白表型开发新的机制，基于生理学的药代动力学， 由体外数据提供信息的定量系统药理学模型将更准确地预测 改变药物处置的肝脏转运。这些信息对于优化治疗结果至关重要。