The failure of aldose reductase inhibitor 3,3′-tetramethylene glutaric acid to inhibit in vivo sorbitol accumulation in lens and retina in diabetes

Abstract

The aldose reductase inhibitor, 3,3′-tetramethylene glutaric acid was investigated as a potential agent to inhibit the accumulation of sorbitol pathway intermediates in various tissues of the rat in diabetes. Two modes of administration were used; the feeding of a 1% (w/v) solution of the disodium salt of the drug; and the injection of the drug three times daily by an intraorbital extra-ocular route. Neither treatment prevented the accumulation of sorbitol and fructose in retina or lens tissue in the diabetic state. A gas chromatographie method for the analysis of TMG in biological material was developed and applied to the study of the pharmacological properties of the drug. The half-life of the drug in rabbit after a single intravenous injection was 22 min. It was apparent that plasma membranes were impermeable to TMG and it was not possible to achieve significant concentrations of the drug in lens or retinal tissue by its administration orally or intraorbitally. It is concluded that disodium TMG could not be used as an in vivo inhibitor of sorbitol pathway activity in retina or lens in diabetes, and that its systemic use to inhibit sorbitol pathway activity in other tissues is not practical.