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 #
5R01GM041935-20
Application #
8307954
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
2012-07-01
Budget End
2013-06-30
Support Year
20
Fiscal Year
2012
Total Cost
$560,606
Indirect Cost
$150,038
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
Ferslew, Brian C; Brouwer, Kim L R (2014) Identification of hepatic phospholipidosis inducers in sandwich-cultured rat hepatocytes, a physiologically relevant model, reveals altered basolateral uptake and biliary excretion of anionic probe substrates. Toxicol Sci 139:99-107
Pfeifer, Nathan D; Hardwick, Rhiannon N; Brouwer, Kim L R (2014) Role of hepatic efflux transporters in regulating systemic and hepatocyte exposure to xenobiotics. Annu Rev Pharmacol Toxicol 54:509-35
Lauffenburger, Julie C; Mayer, Christina L; Hawke, Roy L et al. (2014) Medication use and medical comorbidity in patients with chronic hepatitis C from a US commercial claims database: high utilization of drugs with interaction potential. Eur J Gastroenterol Hepatol 26:1073-82
Yang, K; Woodhead, J L; Watkins, P B et al. (2014) Systems pharmacology modeling predicts delayed presentation and species differences in bile acid-mediated troglitazone hepatotoxicity. Clin Pharmacol Ther 96:589-98
Kock, Kathleen; Ferslew, Brian C; Netterberg, Ida et al. (2014) Risk factors for development of cholestatic drug-induced liver injury: inhibition of hepatic basolateral bile acid transporters multidrug resistance-associated proteins 3 and 4. Drug Metab Dispos 42:665-74
Powell, John; Farasyn, Taleah; Köck, Kathleen et al. (2014) Novel mechanism of impaired function of organic anion-transporting polypeptide 1B3 in human hepatocytes: post-translational regulation of OATP1B3 by protein kinase C activation. Drug Metab Dispos 42:1964-70
Griffin, LaToya M; Watkins, Paul B; Perry, Cassandra H et al. (2013) Combination lopinavir and ritonavir alter exogenous and endogenous bile acid disposition in sandwich-cultured rat hepatocytes. Drug Metab Dispos 41:188-96
Pfeifer, Nathan D; Bridges, Arlene S; Ferslew, Brian C et al. (2013) Hepatic basolateral efflux contributes significantly to rosuvastatin disposition II: characterization of hepatic elimination by basolateral, biliary, and metabolic clearance pathways in rat isolated perfused liver. J Pharmacol Exp Ther 347:737-45
Yang, Kyunghee; Kock, Kathleen; Sedykh, Alexander et al. (2013) An updated review on drug-induced cholestasis: mechanisms and investigation of physicochemical properties and pharmacokinetic parameters. J Pharm Sci 102:3037-57
Swift, Brandon; Nebot, Noelia; Lee, Jin Kyung et al. (2013) Sorafenib hepatobiliary disposition: mechanisms of hepatic uptake and disposition of generated metabolites. Drug Metab Dispos 41:1179-86

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