Transport proteins play a key role in the disposition, efficacy and toxicity of many drugs. Substantial advances have been made in the field of drug transport. However, the interplay of drugs, bile acids, and hepatic transport proteins in health and disease remains poorly defined. Understanding the factors that influence hepatic drug disposition is often critical to achieve desirable therapeutic outcomes. For example, patients with nonalcoholic steatohepatitis (NASH) show marked changes in hepatic bile acid composition and transporter expression, which may alter drug disposition and predispose NASH patients to treatment failure and/or toxicity. Drug- mediated inhibition of hepatic bile acid efflux is a mechanism of cholestatic drug-induced liver injury (DILI), a serious adverse reaction that frequently terminates development programs for new drug candidates. Although the major human transporters involved in hepatic bile acid efflux have been identified, to date this knowledge has not resulted in accurate predictions of DILI liability or patient susceptibility. The objective of this ongoing research program is to elucidate mechanisms and consequences of transporter-mediated changes in the hepatic disposition of anionic drugs/metabolites and bile acids, and to use this knowledge to predict therapeutic and adverse responses to medications. Research in the current funding period has established novel approaches using human sandwich-cultured hepatocytes to elucidate hepatic transporter function and mechanisms of altered drug/bile acid disposition. Importantly, characterization of phenotypic transporter probes now allows translation of cell-based research to the clinic. Our multidisciplinary translational research team is uniquely positioned to achieve the proposed aims by integrating multiple experimental approaches: clinical phenotypic probe studies, metabolomic profiling, pharmacophore and quantitative structure-activity relationship modeling, genetic analyses from the largest DILI DNA bank worldwide, transporter assays, and mechanistic modeling.
Aim 1 will test the hypothesis that clinically important alterations in drug exposure associated with NASH reflect hepatic transporter dysregulation;phenotypic transporter probes and changes in the serum bile acid metabolome, incorporated as a predictive correlate, will be evaluated.
In Aim 2, computational modeling will identify structural features of compounds associated with hepatic bile acid efflux transporter inhibition. Moreover, the functional impact of genetic variants in ABC transporters enriched in DILI patients will be assessed to test the hypothesis that polymorphisms increase DILI risk by affecting bile acid efflux transporter activity or susceptibiliy to drug inhibition.
Aim 3 will focus on development of novel strategies to predict DILI by incorporating drug-induced changes in bile acid disposition and the bile acid metabolome measured in human sandwich-cultured hepatocytes into a mechanistic, mathematical model. The proposed studies will advance knowledge of the interplay between drugs, bile acids and hepatic transporters, and enhance our capabilities to achieve desirable therapeutic outcomes in patients with hepatic transporter dysregulation.
Hepatic transport proteins are influential in determining drug exposure, efficacy, and harmful side effects such as liver toxicity. These studies will provide new mechanistic information and predictive tools to address how disease, genetic variation, and drugs can cause changes that impact the handling of medications by the liver. This research will contribute to timely, more cost-effective development of safer medications with improved therapeutic outcomes.
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