KINETICS OF THE TISSUE DISTRIBUTIONS OF SULINDAC AND METABOLITES - RELEVANCE TO SITES AND RATES OF BIOACTIVATION

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  • 1 January 1980
    • journal article
    • research article
    • Vol. 8  (4) , 241-246
Abstract
Sulindac (sulfoxide) [Z-5-fluoro-2-methyl-1-[p-(methylsulfinyl)benzylidene]indene-3-acetic acid], a nonsteroid antiinflammatory agent used to treat a variety of rheumatic disorders, is a prodrug in reversible metabolic equilibrium with its pharmacologically active metabolite, the corresponding sulfide. Following simultaneous parenteral injection of sulfoxide-14C and sulfide-3H at equivalent dosage, all labeled species in the plasma of rats and guinea pigs, and in representative tissues, were determined at various times. Rate constants for sulfoxide .dblarw. sulfide, calculated from the rates of interchange of the 2 labels in plasma, are still higher than those approximated from earlier, single-label studies; this indicates turnovers of total body pools every 45 and 8.5 min in rat and guinea pig, respectively. From the time-course of tissue/plasma ratios of endogenous labeled species, it can be concluded that kidney and liver are major sites of bioactivation of the prodrug, with significant sulfoxide .fwdarw. sulfide activity present in all tissues examined. At steady state, tissue concentrations of each redox form are determined by the ratio of the metabolic rate constants for the 2 opposing biotransformations, and by unique tissue/plasma distributive constants for each redox form; this results in all tissues, except lung, and at all times examined in a sulfide/sulfoxide ratio > 1.