Schneider R P, Fouda H G, Inskeep P B
Drug Metabolism Department, Central Research Division, Pfizer Inc., Groton, CT 06340, USA.
Drug Metab Dispos. 1998 Nov;26(11):1149-59.
Zopolrestat (Alond) is a new drug that is being evaluated as an aldose reductase inhibitor for the treatment of diabetic complications. 14C-labeled zopolrestat was orally administered to rats for a tissue distribution study and a bile duct cannulation metabolism study. Tissue samples from the distribution study were analyzed by complete oxidation and liquid scintillation counting. Urine and bile samples from the bile duct cannulation study were analyzed by microbore HPLC, with simultaneous radioactivity monitoring and atmospheric pressure ionization tandem mass spectrometry. The mass balance in the distribution study demonstrated that the greatest exposure (AUC0-infinity) occurred in the liver, followed by the ileum and large intestine. The time of maximal plasma concentrations for nearly all tissues was 4 hr after the dose, and the half-life of radioactivity in most tissues (8-10 hr) was similar to the half-life in plasma. For the bile duct-cannulated rat study, most of the radioactivity was recovered in the bile, indicating that biliary excretion is a major route of elimination of zopolrestat and its metabolites in rats. Numerous oxidative metabolites, as well as phase II conjugates, were identified in the bile and urine samples. Acyl glucuronides of zopolrestat and unchanged drug accounted for >85% of biliary radioactivity, whereas unchanged drug and degradation products of glutathione conjugates were identified as the major urinary metabolites.
唑泊司他（Alond）是一种新型药物，正作为醛糖还原酶抑制剂进行评估，用于治疗糖尿病并发症。将14C标记的唑泊司他口服给予大鼠，进行组织分布研究和胆管插管代谢研究。分布研究的组织样本通过完全氧化和液体闪烁计数进行分析。胆管插管研究的尿液和胆汁样本通过微径高效液相色谱进行分析，同时进行放射性监测和大气压电离串联质谱分析。分布研究中的质量平衡表明，最大暴露量（AUC0-无穷大）出现在肝脏，其次是回肠和大肠。几乎所有组织的最大血浆浓度时间为给药后4小时，大多数组织中放射性的半衰期（8-10小时）与血浆中的半衰期相似。对于胆管插管大鼠研究，大部分放射性在胆汁中回收，表明胆汁排泄是唑泊司他及其代谢产物在大鼠体内的主要消除途径。在胆汁和尿液样本中鉴定出了许多氧化代谢产物以及II相缀合物。唑泊司他的酰基葡萄糖醛酸苷和未变化的药物占胆汁放射性的>85%，而未变化的药物和谷胱甘肽缀合物的降解产物被鉴定为主要的尿液代谢产物。
