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 l-1 (+/- SD), p less than 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 l-1 vs 1.79 +/- 0.67, 1.68 +/- 0.65, and 1.57 +/- 0.59 mg l-1 respectively, p less than 0.005) and 24 h post-dose (1.57 + 0.45 vs 2.01 + 0.73 mg l-1, p less than 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 l-1 2-h-1 to 1.47 +/- 0.30, 1.76 +/- 0.41, and 4.12 +/- 0.72 mg l-1 2-h-1 respectively, p less than 0.01. Galactitol accumulation rate appeared to be a less variable parameter than erythrocyte sorbitol and was not influenced by fluctuations in blood glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
Airey
C M
CM
University Department of Medicine, Leeds, UK.
Price
D E
DE
Kemp
J V
JV
Perkins
C M
CM
Wales
J K
JK
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000097:blood*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D004311:Double-Blind Method; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D004376:Galactitol / Q000097:blood*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007294:Inositol / Q000097:blood*; D010793:Phthalazines / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D013012:Sorbitol / Q000097:blood*; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*; D013402:Sugar Alcohols / Q000097:blood*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D010793:Phthalazines; D011724:Pyridazines; D013402:Sugar Alcohols; D004376:Galactitol; C042829:ponalrestat; D007294:Inositol; D013012:Sorbitol; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase