Hockwin O, Müller P, Krolczyk J, McCue B A, Mayer P R
Department of Experimental Ophthalmology, University of Bonn, FRG.
Ophthalmic Res. 1989;21(4):285-91. doi: 10.1159/000266871.
Investigations on the disposition of the highly effective aldose reductase inhibitor AL01576 were carried out in pigmented rats after oral dosing and topical administration of a 0.1% ophthalmic suspension by means of an assay modified from a previously described method measuring aldose reductase activity. The crude enzyme extract of pig lenses was used as a test system. From the activity remaining after addition of the plasma or lens extracts, the concentration could be determined since the inhibition constant (IC50) of AL01576 is known. With this procedure, the concentration of AL01576 in plasma and lenses of Brown-Norway rats given different doses of the drug for 42 consecutive days were determined and compared with a gas chromatographic assay technique. These data indicate that AL01576 is absorbed into the lens with a substantial portion redistributing into the lens following systemic delivery. Drug concentrations were correlated with efficacy measurements, though they were lower in an animal group treated with naphthalene to provoke cataract formation. In a second animal series with Brown-Norway rats over 5 days, AL01576 was administered three times per day to the right eye only. During the washout period, AL01576 had a long persistence in plasma and lenses following this short-term topical ocular administration.
采用一种基于先前描述的测量醛糖还原酶活性方法改进的测定法，对高效醛糖还原酶抑制剂AL01576在色素沉着大鼠口服给药以及局部给予0.1%眼用混悬液后的处置情况进行了研究。猪晶状体的粗酶提取物用作测试系统。由于已知AL01576的抑制常数（IC50），通过加入血浆或晶状体提取物后剩余的活性，可以确定其浓度。采用该方法，测定了连续42天给予不同剂量药物的棕色挪威大鼠血浆和晶状体中AL01576的浓度，并与气相色谱测定技术进行了比较。这些数据表明，AL01576被吸收进入晶状体，在全身给药后有很大一部分重新分布到晶状体中。药物浓度与疗效测量值相关，不过在萘诱发白内障形成的动物组中药物浓度较低。在另一组为期5天的棕色挪威大鼠实验中，仅对右眼每天给药3次AL01576。在洗脱期，短期局部眼部给药后，AL01576在血浆和晶状体中持续存在的时间较长。
