Influence of Renal and Hepatic Failure on the Pharmacokinetics of Recombinant Human Granulocyte Colony-stimulating Factor (KRN8601) in the Rat

The pharmacokinetics of recombinant human granulocyte colony-stimulating factor (rhG-CSF) was studied in rats experiencing renal and hepatic failure. The serum concentration of rhG-CSF after i.v. administration to male Sprague-Dawley rats at a dose of 10 micrograms/kg was investigated by a sandwich enzyme immunoassay. Total-body clearance of rhG-CSF was 44.48 ml/h/kg in sham-operated rats compared with 9.429 ml/h/kg in bilaterally nephrectomized rats. In sham-operated rats, the half-life (beta) of rhG-CSF was 1.512 h, and it increased to 5.333 h after nephrectomy. The volumes of distribution were identical in both rats. In rats with acute renal failure induced by uranyl nitrate, the clearance and volume of distribution were identical to those of control rats, but the half-life (beta) was slightly shorter. In partially (70%) hepatectomized rats, the clearance of rhG-CSF decreased from 42.08 ml/h/kg to 31.93 ml/h/kg. Similar half-lives were observed in rats in both the sham-operated and hepatectomized groups. However, the volume of distribution decreased after hepatectomy. In rats with hepatic failure induced by CCl4, the pharmacokinetic changes were similar to those observed in hepatectomized rats. These results suggest that renal clearance makes a major contribution to total-body clearance compared with hepatic clearance.