ALTERED HEPATIC DISPOSITION OF ANIONIC DRUGS--MECHANISM

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Altered hepatic disposition of xenobiotics secondary to chemical exposure or physiologic variations has both pharmacologic and toxicologic implications. Inhibition of hepatic uptake of drugs or toxic compounds may prolong pharmacologic activity or enhance systemic toxicity. Likewise, inhibition of hepatic excretion of metabolically activated compounds may delay onset of pharmacologic effect or increase hepatotoxicity. The goal of the proposed research is to examine chemical-induced alterations in the hepatic translocation of organic anions, elucidate the mechanisms of these interactions, and identify structural and physicochemical features associated with perturbations in specific hepatic translocation processes. Perturbations in hepatobiliary disposition of three model organic anion substrates (acetaminophen, indocyanine green, and valproic acid) will be induced by selected probes (phenobarbital and probenecid). A multiexperimental approach will be utilized to define the site(s) and mechanism(s) of these perturbations. The degree to which probes alter overall hepatobiliary disposition of substrates/derived metabolite(s) will be quantitated in the isolated perfused rat liver. Probe-associated alterations in hepatic uptake and egress will be characterized in isolated hepatocytes, and the effect of probes on processes involved in hepatocellular translocation of substrates will be assessed in metabolic and cytosolic protein binding studies. Preliminary data indicate that altered heptobiliary disposition of acetaminophen by the probes is due to interactions with the glucuronide conjugate at the canalicular site. To test this hypothesis, the transport of acetaminophen glucuronide in canalicular rat liver plasma membrane vesicles will be characterized in the absence and presence of probes. Furthermore, the hypothesis that physicochemical properties (lipophilicity, steric factors and/or pKa) of probes determine the extent of perturbation in hepatobiliary disposition of the substrates will be tested using a series of structurally related, but physicochemically distinct, analogs of each of the probes. Based on this information, structure-hepatobiliary transport interaction relationships will be developed, and the specificity of carriers involved in the hepatic transport of the model organic anions will be examined. Elucidation of the mechanisms involved in hepatic translocation of organic anions, and a knowledge of how xenobiotic interactions may alter these processes, is fundamental to understanding how the liver disposes of endogenous and exogenous compounds, and is a prerequisite to exploiting these 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.