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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 study the pharmacokinetics, tissue distribution and excretion of recombinant human endostatin (rhEndostatin) intravenously in rats. Methods 125I labeled rhEndostatin tracer method was used to determine the biological activity of radioimmunoassay (RA) and trichloroacetic acid-radioactivity (TCA-RA) to study the process of drug metabolism. Results After administration of 5, 10 and 20 mg / kg rhEndostatin intravenously, the area under the serum concentration-time curve (AUC) increased with the increase of dose. The level of TCA-RA The half-life (t1 / 2β) and the systemic clearance (CL) of the three doses did not change much, and t1 / 2β was (243-265 min) and CL was (2.4-2.6 mL. kg-1.min-1). After intravenous injection of rhEndostatin 10 mg / kg, the content of the drug in the kidney, the brain, muscle and fat were the lowest. The accumulated urine excretion in 96 h accounted for 86.9% of the total dose, 5.8% of the dose was recovered in the feces and 92.7% of the total excreted in urine and feces within 24 h; 1.3% of the dose. Conclusions After intravenous injection of rhEndostatin in different doses, the drug elimination basically conforms to the linear dynamic characteristics. The distribution of tissue was specifically targeted distribution (with the highest content of the drug in the kidney), and basically reflected the elimination of rhEndostatin mainly by the way of excretion of urine by the kidneys .