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目的评价聚乙二醇化修饰对降纤酶在大鼠体内药动学参数的影响。方法大鼠静脉注射不同剂量~(125)I标记的聚乙二醇化降纤酶(PEG-降纤酶),于给药后各时间点采集血样、尿粪样本和胆汁样本,并于不同时间点处死的大鼠脏器样本,采用总放射性法和三氯醋酸(TCA)沉淀法观察PEG-降纤酶在大鼠体内的血药浓度及组织分布,药物体内半衰期以及药-时曲线下面积(AUC)等药动学参数。结果大鼠静脉注射3种剂量(2、6和18U/kg)PEG-降纤酶,其药-时曲线符合:室模型特征,平均分布半衰期(t_(1/2a))分别为(1.13±0.57)、(1.52±0.96)和(1.99±0.71)h:平均消除半衰期(t_(1/2β))分别为(19.37±1.68)、(20.73±3.99)和(21.14±3.98)h;AUC与剂量呈正相关(r=0.999 3):大鼠静脉注射PEG-降纤酶6 U/kg,药物迅速进入血液循环,与血浓度比较,组织中含量相对较低,药物进入体内主要分布于肾、肺、肝、心、卵巢、脾、胃、大肠、小肠和膀胱等,0.5 h达血药峰浓度;PEG-降纤酶主要随尿液排泄,144 h内尿液、粪便和胆汁的排泄率分别为给药剂量的91.33%、6.74%和4.57%。结论与未经修饰的原型降纤酶相比,经PEG修饰的降纤酶t_(1/2β)延长,可达到长效目的 。
Objective To evaluate the effect of PEGylation on the pharmacokinetic parameters of defibrase in rats. Methods Different doses of 125I-labeled pegylated defibrase (PEG-defibrase) were intravenously injected into the rats and blood samples, urine samples and bile samples were collected at different time points after administration. At the same time, the plasma concentration and tissue distribution of PEG-defibrase in rats were observed by total radioactive and TCA precipitation methods. The half-life of the drug and the area under the drug-time curve (AUC) and other pharmacokinetic parameters. Results The pharmacokinetics of PEG-defibrase at three doses (2, 6 and 18 U / kg) were intravenously injected into rats. The drug-time curve was in accordance with the model of ventricular model and the mean half-life (t 1 / 2a) 0.57), (1.52 ± 0.96) and (1.99 ± 0.71) h respectively. The mean elimination half-life (t 1/2 1/2) were 19.37 ± 1.68 and 20.14 ± 3.99, The dose was positively correlated (r = 0.999 3): rats intravenous injection of PEG-defibrase 6 U / kg, the drug quickly into the blood circulation, compared with the blood concentration, tissue content is relatively low, the drug mainly into the body in the kidney, Spleen, stomach, large intestine, small intestine and bladder, and reached the peak of blood serum concentration within 0.5 h. The excretion rate of urine, feces and bile in 144 h Respectively, the dose of 91.33%, 6.74% and 4.57%. Conclusion Compared with the unmodified prototype defibrase, PEG-modified defibrase t_ (1/2) prolongs the long-term effect.