Gastric antisecretory effect of FRG-8813, a new histamine H2 receptor antagonist, in rats and dogs.
FRG-8813, a new histamine H2 receptor antagonist, was examined for antisecretory effects and compared with famotidine and cimetidine in rats and dogs. In pylorus-ligated and lumen-perfused rats, FRG-8813 given i.v. reduced basal gastric acid secretion and the acid secretion evoked by histamine, tetragastrin, bethanechol, and 2-deoxy-D-glucose in a dose-dependent manner. The i.v. antisecretory activity of FRG-8813 was equivalent to or slightly less than that of famotidine and the intraduodenal (i.d.) activity was greater than that of cimetidine. The duration of action of FRG-8813 was substantially longer than that of farmotidine and cimetidine for both i.v. and i.d. routes. The i.v. ED40 values for the histamine- and tetragastrin-evoked responses and the i.v. ED30 value for the bethanechol-evoked response were 0.15, 0.09 and 0.43 mg2kg, respectively. In Heidenhain pouch dogs, when the three H2 antagonists were given i.v. or orally, the relative antisecretory potency of the compounds was similar to that in rats. The long-lasting antisecretory effect of FRG-8813 was also observed, and the i.v. ED50 values for histamine-, tetragastrin- and bethanechol-evoked responses were 0.1, 0.24 and 1.0 mg/kg, respectively. Comparison of the parenteral and enteral potencies indicated that FRG-8813 has a lower bioavailability than famotidine and cimetidine in rats and dogs. These data suggest that FRG-8813 has a potent and long-lasting antisecretory effect with a far greater potency than cimetidine and with a slightly lower potency than famotidine.
Shibata
M
M
Pharmaceuticals Research Laboratories, Fujirebio Inc., Tokyo, Japan.
Yamaura
T
T
Inaba
N
N
Onodera
S
S
Chida
Y
Y
Ohnishi
H
H
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D002927:Cimetidine / Q000494:pharmacology; D004285:Dogs; D015738:Famotidine / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D017442:Histamine Agonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D008026:Ligation; D008297:Male; D010477:Perfusion; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000081:Acetamides; D017442:Histamine Agonists; D006635:Histamine H2 Antagonists; D010880:Piperidines; D011725:Pyridines; C076948:lafutidine; D015738:Famotidine; D002927:Cimetidine; D006632:Histamine