摘要
目的研究大鼠静脉注射重组人内皮抑素(recombinant human endostatin,rhEndostatin)药代动力学、组织分布及排泄。方法采用125I标记rhEndostatin示踪法,测定生物样品总放射性(radioactivity,RA法)和三氯醋酸沉淀蛋白后的放射性(trichloroacetic acid-radioactivity,TCA-RA法)以研究药物代谢过程。结果大鼠静脉注射rhEndostatin 5、10和20 mg/kg后,血药浓度和药物时间曲线下面积(area under the serum concentration-time curve,AUC)均随剂量增加而增大;TCA-RA法测定3个剂量的平均消除半衰期(elimination half-life,t1/2β)和平均清除率(systemic clearance,CL)变化不大,t1/2β为(243～265 min)、CL为(2.4～2.6 mL.kg-1.min-1)。大鼠静脉注射rhEndostatin 10 mg/kg后,以肾脏含药量最高,脑、肌肉和脂肪的含药量最低。96 h内由尿累积排泄量占给药总量的86.9%,粪中可回收到给药量的5.8%,尿和粪的总回收率达到92.7%;24 h内由胆汁排出的药量占给药量的1.3%。结论大鼠静脉注射rhEndostatin不同剂量后,药物消除基本符合线性动力学特征;组织分布呈特异性靶向分布(以肾脏含药量最高),也基本反映了rhEndostatin主要经肾由尿排泄的途径消除。
Objective To characterize the pharmacokinetics,tissue distribution,and excretion profiles of recombinant human endostatin（rhEndostatin） following a single intravenous administration to rats.Methods The rhEndostatin was labeled with 125I and the pharmacokinetics of 125I-rhEndostatin was investigated by two assays： the total radioactivity assay（RA method） and the radioactivity assay after precipitation with trichloroacetic acid（TCA-RA method）.Results The rats were randomly assigned into three groups in which the rats were given intravenously rhEndostatin at doses of 5,10 and 20 mg/kg,respectively.The serum rhEndostatin concentrations and the area under the concentration-time curve（AUC） increased with the dose increment.The serum elimination half-life（t1/2β） and clearance（CL） did not display markedly dose-dependence and were relatively consistent in the range of 243~265 min and 2.4~2.6 mL·kg-1·min-1 using TCA-RA method,respectively.In the rats with 10 mg/kg rhEndostatin（iv）,the levels were the highest in the kidneys,and the lowest in the brain,muscle and adipose tissue.The accumulative excretion percentages of 125I-rhEndostatin from urine and feces reached 86.9% and 5.8% of the administered radioactivity within 96 h,and 1.3% from bile within 24 h,respectively.Conclusion RhEndostatin has linear pharmacokinetic properties within the therapeutic dose range.The rhEndostatin has characteristics of targeting special tissue distribution（the highest level of the drug was found in the kidneys）,which may reflect that urinary excretion is the dominant route of elimination via the kidneys in rats following iv administration of rhEndostatin.
出处
《首都医科大学学报》
CAS
2012年第2期209-213,共5页
Journal of Capital Medical University
基金
国家高新技术发展计划资助项目(2007BAI14IB04)~~
关键词
重组人内皮抑素
药代动力学
组织分布
排泄
大鼠
recombinant human endostatin
pharmacokinetics
tissue distribution
excretion
rat
