摘要
研究猕猴多次 sc重组人血小板生成素(rh TPO) 2 μg· kg-1· d-1× 2 0 d或保护剂白蛋白后药代动力学 ,外周血小板计数及血清 TPO抗体变化 ;通过猴血清对 TD- 3细胞依赖 TPO增殖效应的影响评价抗体性质 .酶联免疫法测定血清 rh TPO浓度表明在第 1 ,7和 2 0次注药后 cmax和 AUC0 -τ随注药次数增加明显降低 ,而 Tp 提前 ,提示 TPO存在时间依赖性非线性过程 .血小板于 d5开始增高 ,d 1 4达峰值 ,d 2 0仍保持较高水平 (2 97±2 7) % .于 d 9- 1 1出现低滴度抗 TPO抗体 ,d 2 1达最高滴度 (1∶ 2 5- 1∶ 1 2 5) .sc TPO和白蛋白后猴血清对 TD- 3依赖 TPO增殖效应均有轻微抑制作用 ,抑制曲线呈非中和抗体性质 .
Drug concentration, peripheral platelet count and anti-thrombopoietin(TPO)-antibodies were studied after sc multi-dosing of recombinant human TPO(rhTPO, 2 μg·kg -1·d -1×20 d) in macaca mulatta and compared with vehicle (albumin) control. The nature of antibodies was studied by means of the inhibitory effect of anti-sera on the TPO-dependent proliferation of TD-3 cells in vitro. Concentration-time curves of TPO determined by ELISA demonstrated that the c max and AUC 0-τ following the 1st, the 7th, and the 20th dosing of rhTPO significantly decreased with dosing (P<0.05). Values of c max were (3.49±1.45), (2.84±1.52), and (1.18±0.24) μg·L -1; while AUC 0-τ were (37.5±13.3), (30.1±15.6), and (13.8±1.5) μg·h·L -1, respectively. Time to peak (T p) brought forward from (4.7±1.2) and (3.3±1.2) to (1.7±0.6) h, respectively. Peripheral platelet counts began to increase on d 5, achieved maximal (404±92)% on d 14, and maintained at high levels (297±27)% on d 20. Low titers of anti-TPO antibodies were detected on d 9-11 and reached their maximal levels of 1∶25-1∶125 on d 21. Inhibitory effect of sera on TPO dose-dependent proliferation of TD-3 cells was not related to treatment (TPO or albumin) or anti-TPO antibody titers, and the dose-response curve was not competitive. The results suggest that there be time-dependent non-linear pharmacokinetics after multi-dosing of rhTPO. Platelet counts was maintained at high level during multi-dosing. Low titer of anti-TPO antibodies was detected, but were not neutralizing antibody.
出处
《中国药理学与毒理学杂志》
CSCD
北大核心
2000年第3期227-231,共5页
Chinese Journal of Pharmacology and Toxicology
基金
国家自然科学基金重点资助项目! (39930 180 )
关键词
重组蛋白
血小板生成素
药代动力学
猕猴
recombinant protein
thrombopoietin
pharmacokinetics
enzyme-linked immuno-sorbent assay
platelet count
antibodies
Macaca mulatta
