Pharmacological effect of recombinant human colony-stimulating factor (rhG-CSF) after administration into rat large intestine

Abstract

The effects of organic acid and nonionic surfactant on the pharmacological activity of recombinant human granulocyte colony-stimulating factor (rhG-CSF) after administration into the large intestine of rats was investigated in comparison with administration into the small intestine. RhG-CSF was administered to rats (50 and/or 100 μg/kg) as solutions in which citric acid and/or polyoxythelated castor oil derivative (HCO-60) were formulated as representative of both organic acid and nonionic surfactant, respectively. Test solutions were administered into the rat ascending colon or duodenum. Blood samples were collected for a 72 h period from the rat tail artery and the blood total leukocyte (BTL) counts were measured as a pharmacological index of rhG-CSF. The results are expressed as a relative increase in BTL counts as compared to the pre-dose level. The area under the curves (AUC; % BTL increase × h) obtained was used as an index for the pharmacological activity of rhG-CSF when comparing the test with the placebo solution. With respect to large intestinal administration, the following observations were made: (1) the effect of citric acid on the pharmacological activity was dependent on the amount of citric acid added to the test solution; (2) HCO-60 exerted a synergistic effect to the critic acid on the pharmacological activity of rhG-CSF; (3) dose-dependent pharmacological activity of rhG-CSF was achieved at 50 and 100 μg/kg. As compared to small intestinal administration, stronger pharmacological activity of rhG-CSF was elicited by administration into the large intestine. These results are in support of the potential use of colonic delivery of rhG-CSF as an oral dosage form.