S. Takakura, H. Minoura, Yukinori Shimoshige
Sep 1, 2001
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Drug Development Research
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 IC50 values of 7.5 and 44 nM, respectively. However, the IC50 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 ED50 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.