# Mechanisms of Altered Hepatic Transport: Impact on Drug Therapy

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $569,357

## Abstract

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development safety issue and reason that approved drugs are withdrawn from the market.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 mode...

## Key facts

- **NIH application ID:** 9906256
- **Project number:** 5R35GM122576-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** KIM L.R. BROUWER
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $569,357
- **Award type:** 5
- **Project period:** 2017-04-05 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906256

## Citation

> US National Institutes of Health, RePORTER application 9906256, Mechanisms of Altered Hepatic Transport: Impact on Drug Therapy (5R35GM122576-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9906256. Licensed CC0.

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