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 increase with an IC50 value of 18 nmol/l. A subsequent experiment showed that fidarestat had a similar inhibitory effect on the increase in sorbitol content 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 glucose, HbA1C, age, aldose reductase content or gender, there was a significant positive relationship between the IC50 value of epalrestat and fasting plasma glucose. In addition, in fidarestat (0.25-2 mg/kg)-treated diabetic 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 pathway flux in target tissue after fidarestat administration. These results suggest that fidarestat potently inhibits the increase in sorbitol pathway flux in diabetic patients independent of various factors and that erythrocyte sorbitol is useful for its estimation.
Sobajima
H
H
Department of Internal Medicine, Ogaki Municipal Hospital, Gifu, Japan.
Aoki
T
T
Sassa
H
H
Suzuki
T
T
Taniko
K
K
Makino
M
M
Mizuno
K
K
Suzuki
T
T
D000367:Age Factors; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003920:Diabetes Mellitus / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005215:Fasting; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D012737:Sex Factors; D013012:Sorbitol / Q000378:metabolism*; D053778:Thiazolidines
D000449:Aldehyde Reductase; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D006442:Glycated Hemoglobin; D007093:Imidazoles; D048289:Imidazolidines; D012236:Rhodanine; D013012:Sorbitol; D053778:Thiazolidines; C038131:epalrestat; C077139:fidarestat