聚乙二醇化降纤酶在大鼠体内的药动学研究  

Pharmacokinetics of PEG-defibrase in rats

作　　者：吴学军[1] 黄晓玲[1] 肖璘[1] 刘珉宇[1] 卢艳萍[1] 刘全海[1] 戴静芝[1] 

机构地区：[1]中国医药工业研究总院上海医药工业研究院创新药物和制药工艺国家重点实验室,上海200437

出　　处：《世界临床药物》2012年第7期401-405,共5页World Clinical Drug

基　　金：上海市科学技术委员会资助项目(编号:08DZ2291400)

摘　　要：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 influence of PEGylation to defibrase on pharmacokinetic parameters in rats. Methods After different dosages of 125I labeled PEG-defibrase were injected to SD rats, the samples of plasma, tissue, urine, feces and bile at various time points were collected and analyzed for total and TCA precipitated radioactivity. Plasma level, tissue distribution, half-life and the dose and area under the curve （AUC） of PEG-defibrase were generated. Results The mean concentration-time curve was fitted to a two-compartment model. When the SD rats were injected with PEG-defibrase at 2, 6 and 18 U/kg, the blood clearance showed that the corresponding mean distribution half-life （t1/2α） were （1.13±0.57）, （1.52±0.96） and （1.99±0.71） h, and the mean elimination half-life （t1/2β） were （19.37±1.68）, （20.73±3.99）and （21.14± 3.98） h, respectively. A linear relationship was found between the AUC with r=0.999 3. After the rats being injected with 6 U/kg, the concentration of PEG-defibrase found in tissues was lower than that in plasma. PEG-defibrase was distributed primarily to kidney, lung, liver, heart, ovary, spleen, stomache, large intestine, small intestine and bladder. The highest PEG- defibrase concentration was observed at 0.5 h. The majority PEG-defibrase was excreted in urine. Additionally, the excretion ratios of the PEG-defibrase in urine, feces and bile at 144 h were 91.33%, 6.74% and 4.57%, respectively. Conclusion Compared with natural defibrase, t1/2β of PEG-defibrase has extended half-life for long-acting.

关 键 词：聚乙二醇化降纤酶 ~125I 药动学 

分 类 号：R972[医药卫生—药品] R969.1[医药卫生—药学]