The inhibition of bovine lens aldose reductase by Clinoril, its absorption into the human red cell and its effect on human red cell aldose reductase activity.
The protein aldose reductase has been implicated in cataract in diabetes and galactosaemia. Recently it has been suggested that a number of non-steroidal anti-inflammatory agents have inhibitory activity against aldose reductase activity, and therefore might be used to prevent diabetic complications including cataract. Steady state kinetic experiments show that Clinoril (Sulindac sulphoxide) acts as a non-competitive inhibitor of NADPH oxidation with purified bovine lens aldose reductase, with an action that may involve binding to more than one site on the protein. As a preliminary to studying the effect on human lens and cataract, a double-masked, placebo-controlled study using random allocation into parallel groups was conducted on 20 volunteers to determine the penetration of Clinoril (Sulindac) and its metabolites into normal human red cells, and the effect of the drug on red cell NADPH-oxidising activity. It was found that while Clinoril, the sulphoxide form of the drug, and its metabolites the sulphone and the sulphide could be detected in the appropriate plasma samples (up to 36 micrograms of the sulphone/ml of plasma), very little could be detected in the red cells. There was no significant effect on red cell NADPH-oxidising activity.
D000042:Absorption; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002417:Cattle; D004912:Erythrocytes / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007192:Indenes / Q000494:pharmacology*; D007908:Lens, Crystalline / Q000201:enzymology*; D008297:Male; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*; D013440:Sulfides / Q000097:blood; D013450:Sulfones / Q000097:blood; D013454:Sulfoxides / Q000097:blood; D013467:Sulindac / Q000378:metabolism / Q000494:pharmacology*
D007192:Indenes; D013440:Sulfides; D013450:Sulfones; D013454:Sulfoxides; D013467:Sulindac; D009249:NADP; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase