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目的:研究rsTRAIL在动物体内的组织分布、药代动力学和抗肿瘤作用。方法:采用同位素标记示踪法结合三氯醋酸(TCA)沉淀法研究rsTRAIL在荷瘤小鼠体内的组织分布及粪尿排泄,采用ELISA法测定猕猴血清中rsTRAIL浓度。结果:荷瘤小鼠iv给药后尿液和肺中酸沉放射性最高,皮下肿瘤放射性分布较低,而脑和骨髓最低。猕猴iv注射高、中、低3个剂量(1,5和25 mg.kg-1)rsTRAIL后,AUC0～t分别为(3.7±0.1),(19.7±0.8)和(103.9±5.2)μg.h-1.mL-1,末端t1/2分别为(28.3±1.0),(31.0±0.7)和(33.2±0.9)min。裸鼠肿瘤模型显示该药具有良好的抗肿瘤作用,抑瘤率达到86%。结论:猕猴iv注射不同剂量rsTRAIL后,在给药剂量范围内基本呈线性药代动力学;荷瘤小鼠iv给药后主要经尿排泄,不易通过血脑屏障。rsTRAIL具有良好的体内外抗肿瘤活性。
OBJECTIVE: To study the tissue distribution, pharmacokinetics and anti-tumor effect of rsTRAIL in animals. Methods: Tissue distribution and excretion of rsTRAIL in tumor-bearing mice were studied by isotope labeling and trichloroacetic acid (TCA) precipitation method. The concentration of rsTRAIL in serum of cynomolgus monkeys was determined by ELISA. Results: The tumor-bearing mice showed the highest radioactivity in urine and lungs after iv administration, the lower radioactivity distribution in subcutaneous tumors and the lowest in brain and bone marrow. AUC0 ~ t was (3.7 ± 0.1), (19.7 ± 0.8) and (103.9 ± 5.2) μg, respectively, after iv injection of high, medium and low doses of rsTRAIL into cynomolgus monkeys. h-1.mL-1, the terminal t1 / 2 was (28.3 ± 1.0), (31.0 ± 0.7) and (33.2 ± 0.9) min respectively. Nude mice tumor model shows that the drug has a good anti-tumor effect, inhibition rate reached 86%. Conclusions: Rhesus monkey iv injection of different doses of rsTRAIL basic pharmacokinetics within the dose range; tumor-bearing mice after iv administration mainly by the urine excretion, not easy to cross the blood-brain barrier. rsTRAIL has good antitumor activity in vitro and in vivo.