The key role of transport proteins in the hepatic uptake and excretion of anionic drugs/metabolites is now widely recognized. Important progress during the current funding period has established that altered function of these transport proteins secondary to drug/toxicant interactions, disease states, or genetic predisposition may modulate systemic, intestinal (via bile) and/or hepatic exposure to drugs/metabolites and endogenous compounds, including bile acids. Such functional alterations have important therapeutic or toxicologic implications for some drugs. The long-term objective of this ongoing research program is to advance mechanistic understanding of how changes in transport function influence overall hepatobiliary disposition of anionic drugs/derived metabolites, and to develop tools to predict clinically-relevant outcomes of altered hepatic drug transport. The need for predictive probes/tools is imperative: research in the field of drug transport is still at an early stage, translation of this information to the clinical setting has been limited, and the potential for clinically- significant alterations in hepatic transport of drugs/metabolites is substantial. A multi-experimental approach incorporating state-of-the-art techniques including sandwich-cultured primary rat and human hepatocytes coupled with RNAi to selectively knock down transport proteins, in vitro expression systems, isolated perfused livers from wild-type and transport protein-deficient rodents, an in vivo human protocol using an MRP2 imaging agent as a phenotypic probe to assess hepatic drug transport interactions, and pharmacokinetic modeling/simulation will be employed to elucidate mechanisms and consequences of altered hepatic transport of model anionic drugs/metabolites. Proposed studies will address three key issues: 1) implications of the multiplicity of drug transport proteins on hepatobiliary drug/metabolite disposition in response to impaired transport function, 2) role of transport proteins in drug-induced liver injury, and 3) development of probes/tools to assess transport protein function. Elucidating mechanisms of altered hepatic drug transport, and identifying the functional consequences of those alterations, are prerequisite to exploiting these processes to achieve desirable clinical outcomes.

Public Health Relevance

Transport proteins in the liver remove many drugs from the body, and may significantly influence drug efficacy or toxicity. This research will clarify how these transport proteins work in concert to control accumulation and excretion of drugs in the liver, and the impact of impaired transport function (e.g., by drugs or disease). An important goal is to develop tools to predict and assess altered drug transport in humans. Results of these studies will impact drug development, improve outcomes of drug therapy, and help prevent drug-induced liver injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM041935-21
Application #
8502184
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
1991-04-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
21
Fiscal Year
2013
Total Cost
$534,184
Indirect Cost
$139,916
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Ferslew, B C; Johnston, C K; Tsakalozou, E et al. (2015) Altered morphine glucuronide and bile acid disposition in patients with nonalcoholic steatohepatitis. Clin Pharmacol Ther 97:419-27

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