SEX-DIFFERENCES IN THE PHARMACOKINETICS OF RECOMBINANT HUMAN GRANULOCYTE COLONY-STIMULATING FACTOR IN THE RAT

The pharmacokinetics of recombinant human granulocyte colony-stimulating factor (rhG-CSF) were studied in male and female rats. The serum concentration of rhG-CSF after iv and sc administration to male and female Sprague-Dawley rats at a dose of 5 and 100-mu-g/kg was investigated by a sandwich enzyme-linked immunosorbent assay. After iv administration, AUC and half-lives of rhG-CSF in female rats were smaller than those for male rats. The volume of distribution of rhG-CSF in female rats was not significantly different from that in male rats. After sc administration, AUC, mean residence time, and half-lives of elimination phase in female rats were smaller than those for male rats. The in vitro biological activities of rhG-CSF were investigated using [H-3]thymidine uptake assay in cultures of bone marrow cells obtained from male and female rat femur. Female rat bone marrow cells showed a similar dose-response profile to rhG-CSF to that of male rat bone marrow cells. The effect of rhG-CSF administration in rats was a specific activity on the neutrophil lineage with an increase of neutrophils in peripheral blood. The in vivo effects of rhG-CSF after iv and sc administration to male and female rats at 5 and 100-mu-g/kg doses were determined. After 100-mu-g/kg administration, the neutrophil count in female rats was similar to that in male rats in the early period; however, the neutrophil count in female rats was lower than that in male rats 24 hr after administration. These results indicate the sex differences in pharmacokinetics and the in vivo effects of rhG-CSF and the close relationship between pharmacokinetics and the in vivo effects of rhG-CSF.