ALTERED HEPATIC DISPOSITION OF ANIONIC DRUGS-MECHANISMS

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Altered hepatic disposition of anionic drugs secondary to drug interactions, chemical exposure, disease states or genetic variations has important therapeutic implications. Systemic exposure and duration of pharmacologic activity may be altered substantially by changes in hepatic translocation of drugs. Likewise, altered hepatic transport can influence systemic, hepatic, or intestinal toxicity. The long-term objective of this research program continues to be the development of a mechanistic understanding of how perturbations in hepatic transport influence overall hepatobiliary disposition of anionic drugs and derived metabolites. A multiexperimental approach utilizing in vivo, isolated perfused rat liver, and in vitro cellular systems will be employed to elucidate mechanisms of altered function of hepatic organic anion transport systems. The hypothesis that hepatic canalicular (Mrp2) and basolateral (Mrp3) transporters function in a coordinate fashion to modulate biliary excretion, intrahepatic concentrations and systemic exposure of anionic substrates will be tested. The utility of an in vitro model system to explore mechanisms of altered hepatobiliary transport, including fundamental aspects of transporter regulation and trafficking, and to predict functional consequences, will be evaluated. This model system represents an exciting tool for studying hepatobiliary drug disposition as it maintains hepatocyte polarity and bile canalicular function, allows direct access to the hepatocyte and adjacent biliary compartment, and minimized the use of experimental animals. Extension of this in vitro methodology to human hepatocytes may provide a novel approach to examine hepatic transport mechanisms and drug transport interaction in the human hepatobiliary system. A pilot study to validate a method of quantify biliary excretion in humans will be performed to evaluate in vitro/in vivo correlations. Elucidation of the mechanisms of hepatic organic anion transport, and knowledge of how xenobiotic interactions or physiologic variations alter these processes, is fundamental to understanding how the liver disposes of endogenous and exogenous compounds. This information will facilitate a priori predictions of hepatic xenobiotic/metabolite disposition in response to altered hepatic transport, and is prerequisite to exploiting hepatic transport processes to achieve desirable therapeutic endpoints. The merit of this work is realized when one considers the number of xenobiotics that undergo hepatic elimination, and the potential for alterations in hepatic transport of these agents.