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]) derived from Klebsiella pneumoniae dramatically decreased the biliary excretion of the β-lactam antibiotic cefoperazone (CPZ), which is primarily excreted into the bile via the anion transport system, in rats. The present study was designed to investigate the effect of human recombinant granulocyte colony-stimulating factor (G-CSF), which is reported to be beneficial in experimental models of inflammation, on the pharmacokinetics and biliary excretion of CPZ in rats. CPZ (20 mg/kg of body weight) was administered intravenously 2 h after the intravenous injection of LPS (250 μg/kg). G-CSF was injected subcutaneously at 12 μg/kg for 3 days and was administered intravenously at a final dose of 50 μg/kg 1 h before LPS injection. Peripheral blood cell numbers were also measured. LPS dramatically decreased the systemic and biliary clearances of CPZ and the bile flow rate. Pretreatment with G-CSF enhanced these decreases induced by LPS. The total leukocyte numbers were increased in rats pretreated with G-CSF compared to the numbers in the controls, while the total leukocyte numbers were decreased (about 3,000 cells/μl) by treatment with LPS. Pretreatment with G-CSF produces a deleterious effect against the LPS-induced decrease in biliary secretion of CPZ, and leukocytes play an important role in that mechanism.