| Popis: |
Human epidermal growth factor (hEGF), produced in E. coli with genetic technology, was rectally administered to rats and the immunoreactive plasma concentrations of hEGF were determined periodically. Enzyme immunoassay for hEGF was developed in the present study. To evaluate the enhanced rectal bioavailability of hEGF with the aid of an absorption promoter in a quantitative manner, intravenous and subcutaneous administrations were also performed. When hEGF was administered i.v. at a dose of more than 100 μg/kg, plasma hEGF disappeared biexponentially with half lives of 1–4 min for the α-phase and 14–24 min for the β-phase. However, when administered at a dose of 50 μg/kg, plasma hEGF disappeared monoexponentially with a half life of 1.5 min. The extraordinary dose-dependent pharmacokinetics of hEGF was observed as follows; values of area under the plasma concentration-time curve (AUC) after i.v. administration of hEGF at doses of 50, 100, 200, 500 and 1,000 μg/kg were 0.27, 3,0, 15.7, 70.5 and 129 μg min ml−1, respectively. The AUC values of hEGF administered s.c. were lower than those after i.v. administration, probably due to the degradation of hEGF at the s.c. injection site. However, hEGF administered s.c. as a solution containing 0.2% sodium carboxymethyl cellulose (CMC Na) showed a 100% bioavailability. When hEGF was administered rectally as an aqueous solution (pH 7.9 isotonic Tris-HCl buffer), no absorption was observed irrespective of the presence of the absorption promoter such as sodium caprate in the dosing solution. On the other hand, a marked enhanced rectal absorption by absorption promoter was observed when hEGF was administered as a solution containing sodium caprate and CMC Na. The bioavailability of hEGF administered rectally at a dose of 100 μg/ml/kg was 68.2% in the presence of 100 mM sodium caprate and 1% CMC Na in the dosing solution. Some discussions with respect to the role of CMC Na are also presented. |
