Effect of uremia and anephric state on the pharmacokinetics of sulindac and its metabolites in rats. I. An application of pharmacokinetic model for reversible metabolism.

Plasma levels of sulindac and its metabolites, sulfide and sulfone, were measured in normal, uremic, and anephric rats following concurrent administration of 11C-sulindac and 3H-sulfide (5 mg-eq/kg). A marked decrease in plasma concentration of sulfide was found in uremic rats, while sulindac concentration in these rats was unchanged. In contrast, anephric rats cleared sulindac more slowly than control rats, but had no effect on the sulfide. A pharmacokinetic model for reversible metabolism was used to characterize the kinetic parameters for sulindac----sulfide interconversion system. The intrinsic clearances of unbound drug were calculated for the interconversion and elimination processes. The results indicated that the reduction of sulindac to sulfide is impaired in uremic and anephric rats. The oxidation of sulfide to sulindac was increased in uremic rats, but decreased in anephric rats. Experimental uremia caused a decrease in plasma protein binding of sulindac and sulfide and an increase in the apparent volumes of distribution of the redox species. Anephric state has less effect on plasma protein binding and volume distribution.