Susceptibility of ebiratide to proteolysis in rat intestinal fluid and homogenates and its protection by various protease inhibitors.
In order to estimate the intestinal stability of ebiratide [H-Met(O2)-Glu-His-Phe-D-Lys-Phe-NH(CH2)8-NH2], a novel adrenocorticotropic hormone (ACTH) analogue, after oral administration, the hydrolytic properties of ebiratide were determined in the rat small intestinal fluid and mucosal homogenates. Ebiratide was extremely stable in the rat small intestinal fluid, while it was degraded in various intestinal mucosal homogenates. Regional differences were observed in its proteolytic properties; e.g., the hydrolytic rates of ebiratide in jejunal and ileal mucosal homogenates were 2-3 times faster than that in duodenal and colonic homogenates. Degradation of ebiratide was markedly inhibited by aminoprotease inhibitors such as sodium glycocholate, puromycin, bestatin and bacitracin. These results suggest that co-administration of certain protease inhibitors are useful to improve the stability of ebiratide in the intestine.
Okagawa
T
T
Department of Biopharmaceutics, Kyoto Pharmaceutical University, Japan.
Fujita
T
T
Murakami
M
M
Yamamoto
A
A
Shimura
T
T
Tabata
S
S
Kondo
S
S
Muranishi
S
S
D000324:Adrenocorticotropic Hormone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D000595:Amino Acid Sequence; D000818:Animals; D001826:Body Fluids / Q000201:enzymology; D010450:Endopeptidases / Q000378:metabolism*; D006868:Hydrolysis; D007328:Insulin / Q000378:metabolism / Q000493:pharmacokinetics; D007413:Intestinal Mucosa / Q000201:enzymology; D007422:Intestines / Q000201:enzymology*; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism* / Q000493:pharmacokinetics; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D007328:Insulin; D010446:Peptide Fragments; D011480:Protease Inhibitors; D000324:Adrenocorticotropic Hormone; C057139:ebiratide; D010450:Endopeptidases