Enzyme specificity and tissue distribution of zenarestat, an aldose reductase inhibitor, and its relevance in the use of zenarestat as a therapeutic agent against diabetic neuropathy

✍ Scribed by Shoji Takakura; Hideaki Minoura; Yukinori Shimoshige; Kyoko Minoura; Ikuo Kawamura; Tomoichi Fujiwara; Takashi Saitoh; Fumio Shimojo; Jiro Seki; Toshio Goto

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: English
• Weight: 146 KB
• Volume: 54
• Category: Article
• ISSN: 0272-4391
• DOI: 10.1002/ddr.1201

✦ Synopsis

Abstract

The enzyme specificity and tissue distribution of zenarestat, an aldose reductase inhibitor, was investigated in diabetic rats. Zenarestat inhibited both rat sciatic nerve aldose reductase (AR) activity and recombinant human AR with IC~50~ values of 7.5 and 44 nM, respectively. However, the IC~50~ value for rat aldehyde reductase of zenarestat was 2.4 μM and the compound did not inhibit any other enzymes tested, e.g., enzymes in the glycolytic pathway, NADPH‐dependent enzymes such as nitric oxide synthase and glutathione reductase, at a concentration of 0.1 mM. Two weeks of treatment with zenarestat in diabetic rats reduced sorbitol concentration in sciatic nerve, lens, retina, and renal cortex with ED~50~ values of 6.9, 41.0, 37.6, and greater than 100 mg/kg, respectively. The tissue distribution of zenarestat was higher in the sciatic nerve as compared with lens and retina. Zenarestat also reduced sorbitol concentration in dorsal root ganglia and spinal cord in diabetic rats. These data indicate the relevance of zenarestat as a therapeutic agent for the treatment of diabetic peripheral polyneuropathy. Drug Dev. Res. 54:27–34, 2001. © 2001 Wiley‐Liss, Inc.