title: Pharmacokinetics and pharmacodynamics of recombinant human granulocyte colony-stimulating factor (rhG-CSF) following intranasal administration in rabbits.
abstract: The objective of this study was to evaluate the pharmacokinetics and pharmacodynamics of G-CSF as well as their relationship following intranasal (i.n.) administration of aqueous rhG-CSF preparations with or without additives. In order to achieve a better understanding of the dosage regimen and the effectiveness of intranasally administered rhG-CSF in inducing leukopoiesis, we investigated rhG-CSF absorption and blood leukocyte dynamics with respect to dose in rabbits. RhG-CSF could be absorbed through the nasal cavity of rabbits when rhG-CSF aqueous preparations, especially those containing alpha-cyclodextrin (alpha-CyD) were intranasally administered. We found that serum G-CSF levels and the total count of leukocytes in peripheral blood (total blood leukocyte count) showed a dose-dependent increase with rhG-CSF. The area under the serum G-CSF concentration-time curve (AUC, a pharmacokinetic parameter) and the area under the increased total blood leukocyte count-time curve (AUL, a pharmacodynamic parameter) increased with increase of dose of rhG-CSF administered intranasally. Good agreement was observed between log AUC and AUL; thus, it is concluded that an increase of AUC leads to an increase in effectiveness of rhG-CSF in inducing leukopoiesis in rabbits. A novel rhG-CSF delivery system in the form of i.n. administration of rhG-CSF was thus achieved.
authors.affiliation: Department of Pharmaceutics, Showa College of Pharmaceutical Sciences, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: R
authors.initials: R
authors.lastname: Kikuchi
authors.forename: M
authors.initials: M
authors.lastname: Kiriyama
authors.forename: K
authors.initials: K
authors.lastname: Nakagawa
authors.forename: H
authors.initials: H
authors.lastname: Nomura
authors.forename: K
authors.initials: K
authors.lastname: Maruyama
authors.forename: M
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D003505:Cyclodextrins / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D011817:Rabbits; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D047391:alpha-Cyclodextrins
chemical_list: D003505:Cyclodextrins; D011994:Recombinant Proteins; D047391:alpha-Cyclodextrins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C032613:alpha-cyclodextrin