Mechanisms of Altered Hepatic Transport: Impact on Drug Therapy

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The importance of hepatobiliary transport proteins in medication disposition, safety and efficacy is well recognized. Identifying key hepatic transporters involved in these processes and understanding the factors that impact their function is critical to successful drug development and optimal pharmacotherapy. The overall goal of this research program is to address major knowledge gaps in hepatobiliary drug transport and develop novel strategies to assess and predict the impact of transporter function altered by drug interactions (DIs), genetic variation, and disease. This information is fundamental to the science of precision medicine, and will aid in preventing DIs and drug-induced liver injury (DILI). My laboratory pioneered the use of sandwich-cultured hepatocytes, a powerful in vitro tool now widely used to study hepatobiliary drug transport and hepatic transporter-mediated DIs. We were the first to assess the functional impact of non-alcoholic steatohepatitis- associated increases in hepatic basolateral efflux transporter expression on drug/metabolite disposition in humans, and to utilize human liver scintigraphy data to evaluate a hepatic DI. Our collaborative team is developing computational tools that can be used a priori in early drug development to identify compounds with DILI liability, and we formulated a strategy integrating physiological parameters and experimental data with a quantitative systems pharmacology (QSP) model to evaluate DILI mechanisms. These highly innovative approaches can improve predictions of hepatic transporter-mediated DIs and DILI liability, leading to safer medications. In the current application, we propose to continue translating fundamental molecular and cellular mechanisms to clinical applications by addressing the following key questions: Which hepatic basolateral efflux transporters are critical to bile acid (BA) homeostasis and anionic drug disposition? The role of basolateral transporters (e.g., OSTα/β) in the hepatic and systemic disposition of BAs and anionic drugs/metabolites will be elucidated. This information will enable us to more accurately predict BA-mediated DILI, a major drug development safety issue and reason that approved drugs are withdrawn from the market. How are hepatic basolateral BA and anionic drug efflux transporters regulated? Information is scarce on the interplay of BA exposure, hepatic transporter dynamics, and the regulation of these proteins in humans. We will fill these critical knowledge gaps, which currently compromise accurate predictions of hepatic transporter function, DIs, and BA- mediated DILI. What in vitro, in silico, and in vivo tools could help predict, more efficiently and accurately, the clinical impact of altered transporter function on BA and anionic drug disposition? In vitro assays routinely used to predict transporter-mediated DIs are unable to identify complex interaction mechanisms. Development of novel in vitro tools, in vivo probes, and in silico models will provide a powerfully efficient approach to identify hepatic transporter-mediated DIs, BA-mediated DILI susceptibility factors, and improve prediction accuracy to optimize pharmacotherapy and avoid adverse effects.