ALTERED HEPATIC DISPOSITION OF ANIONIC DRUGS-MECHANISMS

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

The key role of transport proteins in the hepatic uptake and excretion of anionic drugs/metabolites is now widely recognized. Exciting progress during the current funding period has established that altered function of these transport proteins secondary to drug/toxicant/nutrient 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 multiexperimental 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 four key issues: 1) implications of the multiplicity of drug transport proteins on hepatobiliary drug/metabolite disposition in response to impaired transport function, 2) functional significance of hepatic BCRP, 3) role of transport proteins in drug-induced liver injury, and 4) 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.