Dvornik D, Millen J, Hicks D R, Kraml M
Wyeth-Ayerst Research, Princeton, NJ 08543-8000.
J Diabetes Complications. 1994 Jan-Mar;8(1):18-26. doi: 10.1016/1056-8727(94)90006-x.
The clinical efficacy of an aldose reductase (AR) inhibitor in diabetic polyneuropathy depends on its bioavailability at the site(s) of AR in peripheral nerves. Accordingly, the link between the concentration of the AR inhibitor, tolrestat, and the extent of its inhibition of the AR-catalyzed polyol production was investigated in sciatic nerves of galactosemic rats. Tolrestat was administered by gavage (1 x 150 mg/kg, or 5, and 15 mg/kg/day for 15 days to attain steady state as estimated from the 53-h half-life of tolrestat determined in rat nerve); subsequently, at six time intervals, ranging from 4 to 59 days, rats were given access for 4 days to a 20% galactose diet, and killed. At every time point, the composite tolrestat concentration in the nerve correlated with the percentage decrease in nerve galactitol (r = 0.857, p = 0.0015). Because the latter should reflect the extent of nerve AR inhibition by tolrestat, the concentration of "free" tolrestat available at the site(s) of AR in the nerve was estimated from the tolrestat concentration/percent AR inhibition plot obtained in vitro. The estimated amount of tolrestat present at the site(s) of nerve AR represented 0.4% of the composite tolrestat concentration measured in the nerve. The results support the view that the effectiveness of an AR inhibitor in peripheral nerve depends on its pharmacokinetics in the nerve, i.e., on its uptake, nonspecific binding to cellular constituents, and elimination.
醛糖还原酶（AR）抑制剂治疗糖尿病性多发性神经病的临床疗效取决于其在外周神经AR部位的生物利用度。因此，研究了AR抑制剂托瑞司他的浓度与其对AR催化的多元醇生成的抑制程度之间的关系，实验对象为半乳糖血症大鼠的坐骨神经。通过灌胃给予托瑞司他（1×150 mg/kg，或5和15 mg/kg/天，持续15天以达到稳态，这是根据在大鼠神经中测定的托瑞司他53小时半衰期估算得出）；随后，在4至59天的六个时间间隔内，让大鼠连续4天食用20%的半乳糖饮食，然后处死。在每个时间点，神经中托瑞司他的复合浓度与神经半乳糖醇的降低百分比相关（r = 0.857，p = 0.0015）。因为后者应反映托瑞司他对神经AR的抑制程度，所以从体外获得的托瑞司他浓度/AR抑制百分比图估算神经中AR部位可用的“游离”托瑞司他浓度。神经AR部位存在的托瑞司他估计量占神经中测定的复合托瑞司他浓度的0.4%。这些结果支持以下观点：AR抑制剂在周围神经中的有效性取决于其在神经中的药代动力学，即取决于其摄取、与细胞成分的非特异性结合以及消除。
