Studies of Drug Delivery Systems for Granulocyte Colony-Stimulating Factor. Part III. Pharmacodynamics and Pharmacokinetics of Recombinant Human Granulocyte Colony-Stimulating Factor (rhG-CSF) after Administration of a Rectal Dosage Vehicle.

Abstract

The pharmacodynamic activities (leukopoietic effect) and pharmacokinetics of recombinant human granulocyte colony-stimulating factor (rhG-CSF) administered rectally in various doses as hollow-type suppositories were investigated in rabbits. Three kinds of rhG-CSF hollow-type suppositories were employed: suppository I containing rhG-CSF (100-1000 micrograms/kg) in 10 mM acetate buffer solution (ABS) at pH 4.0, suppository II containing rhG-CSF in ABS with alpha-cyclodextrin (alpha-CyD) as an absorption-enhancing agent, and suppository III containing lyophilized rhG-CSF powder. We found that the total count of leukocytes in peripheral blood (total blood leukocyte count) and serum granulocyte colony-stimulating factor (G-CSF) concentration showed a dose-dependent increase. Consequently, the area under the increased total blood leukocyte count-time curve (AUI), an index of pharmacodynamic activity, and the area under the serum G-CSF concentration-time curve (AUC), a pharmacokinetic parameter, increased with an increase in the rhG-CSF dose administered rectally. Good correlation was found between AUL and AUC; thus, it is concluded that an increase in AUC leads to an increase in the effect of rhG-CSF in inducing leukopoiesis in rabbits following rectal administration. We report for the first time the rectal absorption of rhG-CSF using a new rectal dosage vehicle (rhG-CSF hollow-type suppository) and its leukopoietic effect. The rhG-CSF hollow-type suppository is found to be a promising drug delivery system.