Mechanisms of Altered Hepatic Transport: Impact on Drug Therapy

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.

Grant Number: 5R35GM122576-09
NIH Institute/Center: NIH
Principal Investigator: KIM BROUWER