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The pharmacokinetics of zopolrestat, a carboxylic acid aldose reductase inhibitor, were examined in normal male rats dosed intravenously at 2 mg/kg and in normal and streptozotocin-diabetic male rats after oral administration at 50 mg/kg. After oral dosing, Cmax was 127 µg/ml for normal rats and 144 µg/ml for diabetic rats. AUC(0–∞), however, was lower for diabetic rats than for normal rats and plasma half-life was longer in normal rats (8.0 vs 6.6 hr). Half-lives of zopolrestat in nerve, kidney, and lens were longer than plasma half-life and were similar for both diabetic and normal rats. Less than 2% of the dose was excreted in the urine as unchanged zopolrestat during the 48-hr period following dosing by diabetic or normal rats. Protein binding of zopolrestat was less extensive in plasma from diabetic rats than in plasma from normal rats. Similar kinetics were observed in diabetic animals receiving-five daily doses of zopolrestat at 50 mg/kg/day. There was no plasma or liver accumulation of zopolrestat at steady state, consistent with the observed half-lives. However, zopolrestat did accumulate in nerve, kidney, and lens to varying degrees during multiple dosing, reflecting the longer half-lives of zopolrestat in these tissues.