Tolrestat kinetics

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Abstract
The kinetics of tolrestat, a potent aldose reductase inhibitor, were examined. Tolrestat and total 14C (serum concentrations) were measured after dosing normal and diabetic subjects with 14C-labeled tolrestat. In normal subjects, tolrestat was rapidly absorbed and disappearance from serum was biphasic. Distribution and elimination t1/2 (half lives) were .apprx. 2 and 10-12 h, respectively, after single and multiple doses. Unchanged tolrestat accounted for the major portion of 14C in serum. Radioactivity was rapidly and completely excreted in urine and feces in an approximate 2:1 ratio. Findings were much the same in diabetic subjects. In normal subjects, the oral tolrestat kinetics were independent of dose in the 10-800 mg range. Repetitive dosing did not result in unexpected cumulation. Tolrestat was > 99% bound to serum protein; it did not compete with warfarin for binding sites but was displaced to some extent by high tolbutamide or salicylate concentrations.

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