ALTERED HEPATIC DISPOSITION OF ANIONIC DRUGS--MECHANISMS

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Altered hepatic disposition of anionic drugs secondary to drug interactions, chemical exposure, or physiologic variations has pharmacologic and toxicologic implications. Oral drug bioavailability, as well as the duration of pharmacologic activity, may be altered substantially by changes in the hepatic translocation of drugs. Likewise, impaired hepatic uptake or excretion of xenobiotics may enhance systemic or hepatic toxicity. The long- term objective of this research program continues to be the development of a mechanistic understanding of how perturbations in hepatic transport systems influence overall hepatobiliary disposition of anionic drugs. A multiexperimental approach utilizing isolated perfused livers from normal and transport-deficient mutant Wistar rats, as well as rat canalicular liver plasma membrane vesicles, will be employed to test the hypotheses that: (l) the model organic anion acetaminophen glucuronide is transported into bile via the canalicular electrogenic organic anion transporter (cEOAT) rather than the canalicular multispecific organic anion transporter (cMOAT), and (2) probes (phenobarbital, probenecid, and/or metabolites) alter hepatobiliary disposition of cEOAT substrates by competitive inhibition of biliary excretion, whereas probes do not inhibit the biliary excretion of cMOAT substrates. The ability of an in vitro model system that maintains hepatocyte polarity and bile canalicular function to predict probe-associated alterations in hepatobiliary substrate disposition will be evaluated. This model system may become an important tool for studying hepatobiliary drug disposition as it allows direct access to the hepatocyte and adjacent biliary compartment, minimizes the use of experimental animals, and can be applied to healthy or diseased human hepatocytes. Mechanistic information regarding hepatic Phase III detoxification is limited. Elucidation of the mechanisms involved in hepatic translocation of organic anions, and knowledge of how xendbiotic interactions 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 disposition of xenobiotics and metabolites 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 by other drugs, environmental chemicals, or disease states.