PHARMACOKINETICS OF ZENARESTAT, AN ALDOSE REDUCTASE INHIBITOR, IN MALE AND FEMALE DIABETIC RATS

Acute (approximately 1 week) streptozocin-induced male rats have generally been used as a model for changes in drug metabolism in diabetic humans. The effect of acute (approximately 1 week) and chronic (approximately 3 weeks) streptozocin-induced diabetes on the pharmacokinetics of zenarestat was studied in male and female rats. Total clearance of zenarestat significantly increased in male chronic diabetic rats (15.3-->42.2 ml/hr/kg). In female acute and chronic diabetic rats, pharmacokinetic parameters were similar to those in the control. The fraction unbound to plasma protein was increased with time after streptozocin treatment that was not sex-dependent. In male acute and chronic diabetic rats, the urinary excretion increased compared with the control (acute: 1.7-->7.5%; chronic: 1.9-->13.2% of the dose) after the dose with [C-14] zenarestat. It did not change in female acute diabetic rats and decreased in female chronic diabetic rats compared with the control (61.3-->26.2% of the dose). Renal clearance experiments suggested that the decrease in urinary excretion in female chronic diabetic rats is due to a decrease in active secretion. The increase in the urinary excretion in male rats was probably due to a decrease in testosterone levels in the diabetic state.