Sulindac: therapeutic implications of the prodrug/pharmacophore equilibrium.

Sulindac is a prodrug which, following absorption, rapidly attains a metabolic equilibrium with its active pharmacophore, the sulfide metabolite. At the level of the whole body, the reversible interconversion sulindac in equilibrium sulfide, and the differing distributional and excretory properties of each, provide a theoretical basis for the long plasma half-life of active drug and, in animal species, for the favorable gastrointestinal tolerance observed. In all organ cells examined, and in macrophages, enzyme systems mediating each of the opposing biotransformations between prodrug and active sulfide are present: sulindac reductase in the cytoplasm, and the sulfide oxidase activity in microsomes. Estimated metabolic rate constants for intracellular pools are of the order 0.1-0.3 min-1. It is thus proposed that sulfide, which is oxidized to sulindac in the course of scavenging oxidizing radicals generated in inflammatory responses, may be efficiently regenerated in situ.