Mechanisms of Altered Hepatic Transport: Impact on Drug Therapy

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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.