rsTRAIL药代动力学及药效学研究

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。

Pharmacokinetics and antitumor effects of rsTRAIL in animal

Objective: To investigate the tissue distribution,pharmacokinetics and antitumor effects of rsTRAIL in animals.Methods: Radioisotope tracer labeling combined with trichloroacetic acid precipitation method was used to study the tissue distribution and excretion of rsTRAIL in nude mice.ELISA was used to determine the serum concentrations of rsTRAIL in monkey after intravenous administration.Results: The radioactivities were the highest in urine and lung,lower in tumor section,and the lowest in brain and bone marrow.The pharmacokinetic parameters after single iv doses of rsTRAIL(1,5 and 25 mg·kg-1,respectively) in monkey were as follows: AUC0~t were(3.7±0.1),(19.7±0.8) and(103.9±5.2) μg·h-1·mL-1 respectively,and the t1/2 were(28.3±1.0),(31.0±0.7) and(33.2±0.9) min respectively.rsTRAIL showed a good antitumor effect in vivo.The tumor inhibition rate reached 86% at the dose of 25 mg·kg-1.Conclusion: The pharmacokinetics of rsTRAIL in monkey is linear in the range from 1 to 25 mg·kg-1.It is mainly excreted in urine.rsTRAIL can hardly penetrate the blood-brain barrier.It promises to be an effective antitumor agent.