PHARMACOKINETICS OF THE ALDOSE REDUCTASE INHIBITOR TOLRESTAT - STUDIES IN HEALTHY-YOUNG AND ELDERLY MALE AND FEMALE SUBJECTS AND IN SUBJECTS WITH DIABETES

Tolrestat is an aldose reductase inhibitor undergoing clinical trials in diabetic subjects that may reduce the severity of chronic tissue da mage associated with hyperglycemia. These studies were conducted to ev aluate the pharmacokinetics of tolrestat in healthy young and elderly male and female subjects and in young and elderly subjects with diabet es. The drug was administered in a multiple-dose regimen, and steady-s tate parameters were obtained. There were no important gender-related differences, but mean values for apparent oral clearance, renal cleara nce, and corresponding unbound parameters were significantly lower for the elderly healthy subjects than for the young healthy subjects. The drug is highly bound to plasma proteins, and the unbound fraction (0. 75%) did not differ among the subjects. The results from young and eld erly diabetic subjects suggest that diabetes per se has no influence o n tolrestat disposition but that there is an age-related reduction in apparent oral clearance (30 versus 18 ml/hr/kg) and a corresponding in crease in the minimum steady-state plasma concentration (1.2 versus 1. 9 mu g/ml). These data indicate a possible need to reduce the dose of tolrestat in elderly subjects, assuming the same concentration-respons e relationship.