GRANULOCYTE-COLONY-STIMULATING FACTOR ENHANCES ENDOTOXIN-INDUCED DECREASE IN BILIARY-EXCRETION OF THE ANTIBIOTIC CEFOPERAZONE IN RATS

We have recently reported that endotoxin (lipopolysaccharide [LPS]) de rived from Klebsiella pneumoniae dramatically decreased the biliary ex cretion of the p-lactam antibiotic cefoperazone (CPZ), which is primar ily excreted into the bile via the anion transport system, in rats. Th e present study was designed to investigate the effect of human recomb inant granulocyte colony-stimulating factor (G-CSF), which is reported to be beneficial in experimental models of inflammation, on the pharm acokinetics and biliary excretion of CPZ in rats. CPZ (20 mg/kg of bod y weight) was administered intravenously 2 h after the intravenous inj ection of LPS (250 mu g/kg). G-CSF was injected subcutaneously at 12 m u g/kg for 3 days and was administered intravenously at a final dose o f 50 mu g/kg 1 h before LPS injection. Peripheral blood cell numbers w ere also measured. LPS dramatically decreased the systemic and biliary clearances of CPZ and the bile flow rate. Pretreatment with G-CSF enh anced these decreases induced by LPS. The total leukocyte numbers were increased in rats pretreated with G-CSF compared to the numbers in th e controls, while the total leukocyte numbers were decreased (about 3, 000 cells/mu l) by treatment with LPS. Pretreatment with G-CSF produce s a deleterious effect against the LPS-induced decrease in biliary sec retion of CPZ, and leukocytes play an important role in that mechanism .