METABOLISM OF PYRUVATE ESTERS AND THIOESTERS

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DESCRIPTION: A number of pyruvate esters and thioesters have been synthesized and shown to be potentially useful in preventing and treating reperfusion injury and also for preventing hepatic ethanol toxicity when given in pharmacological doses. In this project, the investigators will test the hypothesis that dipruvyl-acetyl glycerol (DPAG), pyruvyl-acetyl- dihydroxyacetone (PADA), and pyruvate N-acetylcysteine ethyl ester (PNACE) can deliver therapeutic levels of pyruvate without causing lactic acidosis and sodium overload. Preclinical studies will be carried out: 1) to scale up the synthesis of these compounds and prepared new analogs of these compounds; 2) to characterize the metabolism and pharmacodynamics of these compounds in rats, dogs and swines; 3) to determine if the cardioprotective effect of pyruvate esters and thioesters are the result from I) anaplerosis if citric acid cycle intermediates, and ii) inhibition of fatty acid oxidation via increased malonyl-CoA; and 4) to characterize in rats and dogs given ethanol, the effect of pyruvate esters and thioesters on ethanol oxidation, perturbation of intermediary metabolism and free radical production.