title: Oral activity of peptide bradykinin antagonists following intragastric administration in the rat.
abstract: This study has investigated the oral activity, following intragastric administration, of three potent and long-acting peptide-based bradykinin antagonists, HOE-140, B9430, and CP-0597, in the anesthetized rat, using bradykinin-induced hypotension. Two of the three bradykinin antagonists, B9430 and HOE-140, but not CP-0597, were found to be active following intragastric administration, producing dose-dependent (1, 3, and 10 mg/kg) and selective inhibition of bradykinin-induced hypotension. At a dose of 10 mg/kg, the inhibition of bradykinin-induced hypotension occurred within 15 min and lasted for at least 2 h, which was the duration of the experiment. HOE-140 and CP-0597, 10 micrograms/kg i.v., produced significant inhibition of bradykinin-induced responses that lasted for 60 min. B9430, 10 micrograms/kg i.v., produced a significantly greater inhibition than HOE-140 and CP-0597, this inhibition being significant for the duration of the experiment (2 h) compared with saline controls. Considering the close chemical structure of CP-0597 compared with HOE-140 and B9430, it is not clear as to why CP-0597 was inactive via the intragastric route. This is the first demonstration of the oral activity of peptide-based bradykinin antagonists following intragastric administration in the rat.
authors.affiliation: Cortech Inc., Denver, CO 80221, USA.
authors.forename: E T
authors.initials: ET
authors.lastname: Whalley
authors.forename: W L
authors.initials: WL
authors.lastname: Hanson
authors.forename: J M
authors.initials: JM
authors.lastname: Stewart
authors.forename: L
authors.initials: L
authors.lastname: Gera
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007022:Hypotension / Q000139:chemically induced; D008297:Male; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C107323:CP 0597; D009842:Oligopeptides; C065679:icatibant; D001920:Bradykinin