Inskeep P B, Reed A E, Ronfeld R A
Drug Metabolism Department, Pfizer Inc., Groton, Connecticut 06340.
Pharm Res. 1991 Dec;8(12):1511-5. doi: 10.1023/a:1015894300247.
The pharmacokinetics of zopolrestat, a carboxylic acid aldose reductase inhibitor, were examined in normal male rats dosed intravenously at 2 mg/kg and in normal and streptozotocin-diabetic male rats after oral administration at 50 mg/kg. After oral dosing, Cmax was 127 micrograms/ml for normal rats and 144 micrograms/ml for diabetic rats. AUC(0-infinity), however, was lower for diabetic rats than for normal rats and plasma half-life was longer in normal rats (8.0 vs 6.6 hr). Half-lives of zopolrestat in nerve, kidney, and lens were longer than plasma half-life and were similar for both diabetic and normal rats. Less than 2% of the dose was excreted in the urine as unchanged zopolrestat during the 48-hr period following dosing by diabetic or normal rats. Protein binding of zopolrestat was less extensive in plasma from diabetic rats than in plasma from normal rats. Similar kinetics were observed in diabetic animals receiving five daily doses of zopolrestat at 50 mg/kg/day. There was no plasma or liver accumulation of zopolrestat at steady state, consistent with the observed half-lives. However, zopolrestat did accumulate in nerve, kidney, and lens to varying degrees during multiple dosing, reflecting the longer half-lives of zopolrestat in these tissues.
对羧酸醛糖还原酶抑制剂唑泊司他的药代动力学进行了研究，分别在正常雄性大鼠静脉注射2mg/kg以及正常和链脲佐菌素诱导的糖尿病雄性大鼠口服50mg/kg后进行观察。口服给药后，正常大鼠的Cmax为127μg/ml，糖尿病大鼠为144μg/ml。然而，糖尿病大鼠的AUC(0-∞)低于正常大鼠，且正常大鼠的血浆半衰期更长（8.0小时对6.6小时）。唑泊司他在神经、肾脏和晶状体中的半衰期长于血浆半衰期，糖尿病大鼠和正常大鼠相似。给药后48小时内，糖尿病或正常大鼠尿液中以未改变的唑泊司他形式排泄的剂量不到2%。糖尿病大鼠血浆中唑泊司他的蛋白结合程度低于正常大鼠血浆。在每天口服50mg/kg剂量的唑泊司他、连续给药5天的糖尿病动物中观察到相似的动力学。稳态时唑泊司他在血浆或肝脏中无蓄积，这与观察到的半衰期一致。然而在多次给药期间，唑泊司他确实在神经、肾脏和晶状体中不同程度地蓄积，这反映了唑泊司他在这些组织中的半衰期更长。
