The anthracycline antibiotics represent a powerful class of antineoplastic drugs with proven clinical utility in the treatment of various leukemias and solid tumors. The anthracyclines exhibit and extended half-life in the circulation, with the liver being a primary site for their elimination. Conditions of compromised hepatic excretory function result in increased host toxicity for a given dose; furthermore, since little is known of the pathways utilized by the anthracyclines for entry into or secretion from the liver cell, techniques presently in existence do not effectively predict the capacity of the liver to eliminate the anthracyclines, nor is there a rational pharmacologic basis for modification of the clinical regimen in the face of compromised hepatic function. The research in this proposal is directed at elucidation of the hepatocellular pharmacokinetics of the anthracyclines utilizing the isolated hepatocyte model, a radiolabeled adriamycin probe and high pressure liquid chromatographic analysis of metabolite formation. These studies will analyze the elements of adriamycin transport into the hepatocyte in terms of the kinetics of drug influx, structural specificity of the transport route, dependence of transport on cationic ligands, extracellular pH, cellular energy stores, sulfhydryl sensitive membrane proteins and microtubular and microfilament function. Intracellular metabolism of adriamycin and daunorubicin will be assessed, and the intracellular accumulation and distribution of adriamycin, daunorubicin and their metabolites will be analyzed and related to such factors as the rate of drug transport into the cell, the nutritional state of the animal and the effects of inducers of microsomal enzyme metabolism. Efflux of drug and metabolites will be evaluated both in the absence and presence of hormonal inducers of efflux to understand the excretory mechanism for these drugs; such factors as the relative rates of efflux of adriamycin and its metabolites and the possible interaction between adriamycin and its derivatives in exit from the cell will be studied. The contribution of other antineoplastic drugs to transport, metabolism and excretion of the anthracyclines and their metabolites will be evaluated. In addition, the dynamic relationship between influx, accumulation, compartmentation, metabolism and efflux of the anthracyclines will be analyzed by computer network thermodynamic modeling.
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