Raskin P, Rosenstock J, Challis P, Ryder S, Mullane J F, Gonzalez R, Hicks D, Smith T, Dvornik D
Clin Pharmacol Ther. 1985 Dec;38(6):625-30. doi: 10.1038/clpt.1985.236.
The effect of the aldose reductase inhibitor, tolrestat, on red blood cell (RBC) sorbitol levels was studied in 23 patients with diabetes after oral dosing with tolrestat, 25 or 100 mg b.i.d. The mean (+/- SE) RBC sorbitol levels (measured 12 hours after the preceding dose) after 3, 7, and 13 days of dosing decreased after both dose levels. After 25 mg tolrestat the RBC sorbitol levels fell from 25.1 +/- 4.0 to 20.0 +/- 5.7 nmol/gm hemoglobin (21%) and after 100 mg tolrestat the level fell from 26.7 +/- 3.7 to 11.4 +/- 1.7 nmol/gm hemoglobin (57%; P less than 0.001). This latter RBC sorbitol concentration is similar to levels in individuals without diabetes. At both dosage levels the maximum decrease in RBC sorbitol levels occurred after only 3 days of dosing. Tolrestat had no effect on plasma glucose or hemoglobin A1 concentrations. The overall mean plasma unbound drug concentration measured 12 hours after 100 mg tolrestat (11.7 +/- 3.0 ng/ml; 3.3 X 10(-8) mol/L) was similar to the median inhibitory level (3 X 10(-8) mol/L) of tolrestat for sorbitol accumulation in human RBCs incubated in a high-glucose medium. Our results demonstrate the systemic bioavailability of tolrestat and its aldose reductase inhibitory activity in erythrocytes of patients with diabetes.
在23例糖尿病患者中，研究了醛糖还原酶抑制剂托瑞司他口服给药（25或100mg，每日两次）后对红细胞（RBC）山梨醇水平的影响。在给药3天、7天和13天后，两个剂量水平下，（在前一剂给药12小时后测量的）平均（±标准误）红细胞山梨醇水平均下降。服用25mg托瑞司他后，红细胞山梨醇水平从25.1±4.0降至20.0±5.7nmol/g血红蛋白（降低21%），服用100mg托瑞司他后，该水平从26.7±3.7降至11.4±1.7nmol/g血红蛋白（降低57%；P＜0.001）。后一红细胞山梨醇浓度与非糖尿病个体的水平相似。在两个剂量水平下，红细胞山梨醇水平的最大降幅仅在给药3天后出现。托瑞司他对血糖或糖化血红蛋白A1浓度无影响。服用100mg托瑞司他12小时后测得的总体平均血浆游离药物浓度（11.7±3.0ng/ml；3.3×10⁻⁸mol/L）与托瑞司他在高糖培养基中孵育的人红细胞中山梨醇积累的中位抑制水平（3×10⁻⁸mol/L）相似。我们的结果证明了托瑞司他在糖尿病患者红细胞中的全身生物利用度及其醛糖还原酶抑制活性。
