The New Generation Of Recombinant Human Granulocyte Colony-stimulating Factor (rhg-csfa) Rat Poison On Behalf Of Dynamics Study

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 100μg/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 studies 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 time of rhG-CSFa was shorter than that of WT G-CSF. Subsequent in vitro whole blood and serum stability studies, the linear slope constants of wild type G-CSF and rhG-CSFa in serum were 19.548 and 13.398, respectively and whereas in plasma were 18.292 and 10.212, respectively. This indicated that the rates of the proteolysis of mutant G-CSFa were much slower than the wild type both in serum and plasma in vitro.Conclusions these studies suggested that rhG-CSFa with a much better stability and higher bioavailability was obtained. The rhG-CSF was more resistant to be proteolysis and maintained a high concentration in vitro and in vivo. The studies also implied that rhG-CSFa was enhanced for its proteolytic-resistant ability and its binding affinity to its receptors. A new generation of recombinant therapeutic drug for leukopenia and neutropenia may be developed from this study.