Pharmacological properties of fidarestat, a potent aldose reductase inhibitor, clarified by using sorbitol in human and rat erythrocytes

We examined the effect of fidarestat on the increase in sorbitol content in erythrocytes from healthy volunteers in vitro. Fidarestat inhibited the in crease with an IC50 value of 18 nmol/l, A subsequent experiment showed that fidarestat had a similar inhibitory effect on the increase in sorbitol con tent in erythrocytes from diabetic patients, On the other hand, epalrestat, the only aldose reductase inhibitor used clinically, inhibited increase in sorbitol content at a concentration over 500-fold higher than fidarestat. Although the IC50 value of fidarestat was not affected by fasting plasma gl ucose, HbA(1C), age, aldose reductase content or gender, there was a signif icant positive relationship between the IC50 value of epalrestat and fastin g plasma glucose. In addition, in fidarestat (0.25-2 mg/kg)-treated diabeti c rats, the inhibitory rate for erythrocyte sorbitol accumulation was well correlated with that for nerve sorbitol accumulation, which indicates that erythrocyte sorbitol is available for assessing the state of sorbitol pathw ay flux in target tissue after fidarestat administration. These results sug gest that fidarestat potently inhibits the increase in sorbitol pathway flu x in diabetic patients independent of various factors and that erythrocyte sorbitol is useful for its estimation. Copyright (C) 2001 S.Karger AG,Basel