Mechanisms of Altered Hepatic Transport: Impact on Drug Therapy

肝脏中的转运蛋白在药物处置和药物个体间变异性中起着关键作用。 回应。肝转运蛋白功能受多种内在和外在因素的影响。了解这些 影响因素和涉及的机制是提高药物治疗安全性和有效性的基础。这个 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 评估和预测肝脏转运蛋白功能改变对药物处置的影响以改善药物处置的策略 治疗效果。我的实验室率先开发了用于量化肝脏药物的体外工具 处置和胆汁排泄，设计了新的策略来解决关于肝脏的关键科学问题 药物转运，并研究胆汁酸(BAS)和肝脏外排转运体之间的相互作用。支撑点 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)在维持肝脏BA动态平衡中的作用及体外药物研究的新方法 OSTα/β的底物和抑制剂，揭示了肝脏转运蛋白的新调节机制，以及 通过在电子计算机模型中发展先进的转运蛋白科学来预测改变药物的临床影响 运输。然而，许多重要的问题仍然没有得到回答。有哪些替代机制 转运蛋白调节影响肝脏药物处置？我们将继续揭示新的机制 运输商监管。使用我们优化的体外系统，我们将识别出改变细胞转运的药物 转运体，阐明转运体介导的药物相互作用(TDIs)涉及磷酸化的调节 并评估这些变化对肝脏转运体功能的影响。哪种新兴的 体外肝脏系统可以促进我们对肝脏转运蛋白机制的理解？我们将评估 3D肝脏器官和单芯片肝脏系统中的肝脏转运，优化转运体的表达，定位， 并在这些系统中发挥作用，并制定策略，使用这些系统在Silico模型中提供信息，以改进 药物处置和TDIS的预测。胆管细胞转运体在肝药中的作用 性情和TDIS？胆管细胞表达肝药物和BA转运体，在肝BA中起关键作用 监管。我们将定义胆管细胞转运蛋白和肝细胞-胆管细胞的作用 毒品处置和TDIs之间的相互作用。将胆管细胞掺入体外肝脏系统可能进一步 加强预测。新工具能否改善转运蛋白功能评估和预测肝脏药物 活体内的性情？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 TDI研究的生物标志物，并探索肝细胞来源的外切体作为一种非侵入性的量化方法 肝转运蛋白表型。新的机制，基于生理的药代动力学，和 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 药物处置对肝脏转运的影响。这些信息对优化治疗结果至关重要。

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.