The effect of subchronic administration of 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526), a novel acid pump antagonist, on gastric acid secretion and gastrin levels in rats.
In the present report, we evaluated the effect of the novel acid pump antagonist 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526) and 2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-1H-benzimidazole (lansoprazole) on rebound gastric acid secretion, using an intragastric dialysis membrane perfusion model and on the serum and antral gastrin level after a 14-day treatment in rats. The effect of CS-526 on gastric acid secretion was almost constant during the 14 days of treatment. After the 14-day treatment, gastric acid secretion had returned to pretreatment levels. However, CS-526 slightly increased and lansoprazole potently increased gastric acid secretion thereafter. In the posttreatment period, the influence on rebound gastric acid secretion by lansoprazole treatment was significant, but that by CS-526 was not. The serum gastrin concentration after the 14-day treatment with CS-526 did not increase significantly, even at 100 mg/kg/day. On the other hand, lansoprazole at 100 mg/kg/day significantly elevated the serum gastrin concentration. After the 14-day treatment with CS-526 at 100 mg/kg/day, the antral gastrin content significantly increased. Lansoprazole at the doses of 30 and 100 mg/kg/day also significantly increased the antral gastrin content after the 14-day treatment. The elevation of the serum gastrin level after the lansoprazole treatment was suppressed by the concomitant administration of CS-526. In conclusion, CS-526 has a potent antisecretory effect on gastric acid secretion without rebound gastric hypersecretion. Moreover, CS-526 had minimal effects on the serum and antral gastrin elevation. It is suggested that these effects on gastric acid secretion and serum gastrin after subchronic treatment with CS-526 would be beneficial in clinical use.
Ito
Keiichi
K
Pharmacology Research Laboratories, Daiichi Sankyo, Co., Ltd., Hiromachi 1-2-58, Shinagawa-ku, Tokyo 140-8710, Japan. ito.keiichi.vz@daiichisankyo.co.jp
Kinoshita
Kazuya
K
Tomizawa
Atsuyuki
A
Morikawa-Inomata
Yuka
Y
Inaba
Fumi
F
Fujita
Yoshifumi
Y
Tabata
Keiichi
K
Shibakawa
Nobuhiko
N
D000818:Animals; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005744:Gastric Acid / Q000378:metabolism*; D005755:Gastrins / Q000032:analysis / Q000097:blood*; D008297:Male; D054328:Proton Pump Inhibitors; D017494:Proton Pumps / Q000097:blood* / Q000378:metabolism; D011724:Pyridazines / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley
C523982:7-(4-fluorobenzyloxy)-2,3-dimethyl-1-((2-methylcyclopropyl)methyl)-1H-pyrrolo(2,3-d)pyridazine; D005755:Gastrins; D054328:Proton Pump Inhibitors; D017494:Proton Pumps; D011724:Pyridazines; D011758:Pyrroles