新型重组人粒细胞集落刺激因子在大鼠体内的药代动力学研究

Pharmacokinetic study of a novel recombinant human granulocyte colony-stimulating factor in rats.

作者信息

Liu Xiao-Xiao, Jiang Yong-Ping

机构信息

Biopharmaceutical R&D Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215126, China.

出版信息

Chin Med Sci J. 2010 Mar;25(1):13-9. doi: 10.1016/s1001-9294(10)60014-4.

DOI:10.1016/s1001-9294(10)60014-4

PMID:20449948

Abstract

OBJECTIVE

To study the pharmacokinetics of a novel recombinant human granulocyte colony-stimulating factor (rhG-CSFa) in rats and to determine the proteolytic rates of rhG-CSFa in the whole blood and serum of rats in vitro.

METHODS

The pharmacokinetics of rhG-CSFa and conventional (wild type, WT) granulocyte colony-stimulating factor (G-CSF) were investigated in Sprague-Dawley rats which received either intravenous or subcutaneous injection of rhG-CSFa or WT G-CSF at three different doses (20, 50, or 100 microg/kg). The blood samples of rats were collected at multiple time points (from 0.08 to 12 h) and the concentrations of rhG-CSFa and WT G-CSF in serum were determined with a sandwich enzyme-linked immunosorbent assay (ELISA). For the study of proteolytic rates in vitro, the concentrations of rhG-CSFa or WT G-CSF were determined at 3-minute intervals after addition of the respective drug to rat's whole blood or serum.

RESULTS

Pharmacokinetic analysis of serum rhG-CSFa or WT G-CSF levels indicated that, at each dose tested, for either route of drug administration, the area under concentration-time curve values and the maximum serum concentration of rhG-CSFa were higher than those of WT G-CSF, and the serum half life of rhG-CSFa was longer than that of WT G-CSF. Subsequent in vitro whole blood and serum stability study showed that the rates of drug degradation in WT G-CSF were 1.8 folds and 1.5 folds higher than those in rhG-CSFa, respectively.

CONCLUSION

rhG-CSFa has better serum and whole blood stability in vitro and higher bioavailability in vivo as compared to WT G-CSF.

摘要

目的

研究新型重组人粒细胞集落刺激因子（rhG-CSFa）在大鼠体内的药代动力学，并测定rhG-CSFa在大鼠全血和血清中的体外蛋白水解率。

方法

在Sprague-Dawley大鼠中研究rhG-CSFa和传统（野生型，WT）粒细胞集落刺激因子（G-CSF）的药代动力学，大鼠分别静脉注射或皮下注射三种不同剂量（20、50或100μg/kg）的rhG-CSFa或WT G-CSF。在多个时间点（0.08至12小时）采集大鼠血样，采用夹心酶联免疫吸附测定法（ELISA）测定血清中rhG-CSFa和WT G-CSF的浓度。为了研究体外蛋白水解率，在将相应药物加入大鼠全血或血清后，每隔3分钟测定rhG-CSFa或WT G-CSF的浓度。

结果

血清rhG-CSFa或WT G-CSF水平的药代动力学分析表明，在每个测试剂量下，无论药物给药途径如何，rhG-CSFa的浓度-时间曲线下面积值和最大血清浓度均高于WT G-CSF，且rhG-CSFa的血清半衰期长于WT G-CSF。随后的体外全血和血清稳定性研究表明，WT G-CSF中的药物降解率分别比rhG-CSFa高1.8倍和1.5倍。