The Effect of Aldose Reductase Inhibition on Erythrocyte Polyols and Galactitol Accumulation in Diabetic Patients

Erythrocyte sorbitol level has previously been used as a measure of the efficacy of aldose reductase inhibitors, but its value is limited by fluctuations related to variations in blood glucose concentration. The aim of the study was to compare sorbitol content with the ability to accumulate galactitol during ex vivo incubation with galactose, of erythrocytes taken from diabetic patients following administration of a single 600 mg dose of the aldose reductase inhibitor, ponalrestat. Twelve patients were studied in a placebo‐controlled crossover trial. Blood glucose levels were not statistically different during the placebo and ponalrestat treatment periods except at 1 h after the dose was taken (10.6 ± 6.7 vs 7.7 ± 4.6 mmol I−1 (±SD), p < 0.05). Ponalrestat reduced erythrocyte sorbitol concentrations compared with placebo at 3, 5 and 7 h (0.82 ± 0.36, 0.69 ± 0.23, and 0.83 ± 0.35 mg I−1 vs 1.79 ± 0.67, 1.68 ± 0.65, and 1.57 ± 0.59 mg I−1 respectively, p < 0.005) and 24 h post‐dose (1.57 + 0.45 vs 2.01 + 0.73 mg I−1, p < 0.05). Ponalrestat also reduced erythrocyte galactitol accumulation at 3, 5 and 24 h post‐dose from 5.53 ± 2.41, 5.43 ± 1.89, and 5.42 ± 1.96 mg I−1 2‐h−1 to 1.47 ± 0.30, 1.76 ± 0.41, and 4.12 ± 0.72 mg I−1 2‐h−1 respectively, p< 0.01. Galactitol accumulation rate appeared to be a less variable parameter than erythrocyte sorbitol and was not influenced by fluctuations in blood glucose. After placebo the intra‐individual coefficient of variation in galactitol accumulation rate was 6.2 % and for erythrocyte sorbitol was 26.3 %. Thus a single 600 mg dose of ponalrestat inhibits erythrocyte aldose reductase in diabetic patients. Inhibition of galactitol accumulation appears to be a method of in vitro assessment of aldose reductase inhibitor efficacy which, unlike erythrocyte sorbitol, is independent of blood glucose levels.