High potency of a new bombesin antagonist (RC-3095) in inhibiting serum gastrin levels; comparison of different routes of administration.
This study was performed to evaluate the efficacy and duration of action of a new bombesin antagonist D-Tpi6,Leu13 psi (CH2NH)Leu14-bombesin (6-14) (RC-3095), given by different routes of administration, in suppressing gastrin releasing-peptide (GRP(14-27))-stimulated gastrin release in rats. First, we showed that GRP(14-27) itself was highly active when administered by different routes. GRP(14-27), given to rats at a dose of 25 micrograms/100 g b.w. significantly increased serum gastrin levels 3 and 6 min after intravenous and for more than 30 min after subcutaneous administration or pulmonary inhalation. RC-3095 was then injected subcutaneously, intravenously and also delivered by pulmonary inhalation at a dose of 10 micrograms/100 g b.w. in each case to seven male rats 2, 30, 60 or 120 min prior to i.v. administration of 5 micrograms GRP(14-27). RC-3095 administered 2 min prior to GRP(14-27) decreased the gastrin response to GRP(14-27), measured as area under the curve, by 81% in the intravenously injected group and 64% in the pulmonary inhalation group in the first 6 min. When GRP(14-27), was given 30 min after administration of RC-3095, the gastrin response was decreased by 52% in the subcutaneous group, 49% in the pulmonary inhalation group and 11% in the intravenous group during the first 6 min. RC-3095 delivered subcutaneously or by pulmonary inhalation 1 h before GRP(14-27) was also able to significantly inhibit gastrin release. Analysis of the data revealed that the bioavailability of RC-3095 given by the pulmonary inhalation route was about 69% of the s.c. route.(ABSTRACT TRUNCATED AT 250 WORDS)
Pinski
J
J
Endocrine, Polypeptide and Cancer Institute, VA Medical Center, New Orleans, LA 70146.
Yano
T
T
Rekasi
Z
Z
Cai
R Z
RZ
Radulovic
S
S
Schally
A V
AV
D000280:Administration, Inhalation; D000818:Animals; D001839:Bombesin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019886:Gastrin-Releasing Peptide; D005755:Gastrins / Q000097:blood*; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D010455:Peptides / Q000037:antagonists & inhibitors*; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley
D005755:Gastrins; D010446:Peptide Fragments; D010455:Peptides; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; D019886:Gastrin-Releasing Peptide; C041922:gastrin releasing peptide (14-27); D001839:Bombesin