Effect of SG-210, a novel aldose reductase inhibitor, on impaired polyol pathway in rats received diabetic manipulations.
To investigate the effect of SG-210, a potent inhibitor selective to aldose reductase (ARI), on the impaired polyol pathway, we examined biochemically and histologically the potencies of this compound in streptozotocin-induced diabetic or galactosemic rats. The study with diabetic rats showed that SG-210 (1-10 mg x kg(-1)) dose-dependently inhibited sorbitol accumulations in erythrocytes, sciatic nerves, lens, and retina with ED50 values of 1.4, 1.3, 3.5, and 4.6 mg x kg(-1), respectively. Zenarestat, currently under clinical trials both in Japan and the United States, was about two or over five times less potent than SG-210 in suppressing sorbitol contents of erythrocytes or other tissues, respectively. Epalrestat, commercially available, was much less potent in reducing the contents with ED50 values of more than 30 mg x kg(-1) in all of the cells and the tissues examined. An extensive study using galactosemic rats indicated that SG-210 (3-30 mg x kg(-1)) inhibited galactitol accumulations in lens and retina as well as in erythrocytes, preventing the progression of histological abnormalities in lens accompanied by the reduction in galactitol contents. Epalrestat (3-30 mg x kg(-1)) failed to show any significant effects. Pharmacokinetic studies suggested that SG-210 has a high bioavailability and possesses a long half-life in rats (ca. 10 h). Taken together with its excellent pharmacokinetic profiles, the potent suppressive effects of SG-210 observed in this study may be available as a new treatment of diabetic complications.
Horie
S
S
Pharmacology Research Division, The Green Cross Corporation, Hirakata, Osaka, Japan.
Nagai
H
H
Yuuki
T
T
Narita
Y
Y
Tsuda
Y
Y
Nakajima
T
T
Nakamura
N
N
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D052160:Benzothiazoles; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003930:Diabetic Retinopathy / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000378:metabolism; D004376:Galactitol / Q000378:metabolism; D005693:Galactosemias / Q000378:metabolism; D007908:Lens, Crystalline / Q000378:metabolism / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D012160:Retina / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism; D013402:Sugar Alcohols / Q000378:metabolism*; D013843:Thiazines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D011799:Quinazolines; D013402:Sugar Alcohols; D013843:Thiazines; D013844:Thiazoles; C064920:FR 74366; D004376:Galactitol; C088258:SPR 210; D013012:Sorbitol; D000449:Aldehyde Reductase