The long-lasting effect of TU-199, a novel H+, K(+)-ATPase inhibitor, on gastric acid secretion in dogs.

Abstract

We have used Heidenhain-pouch dogs to investigate the effects of (+/-)-5-methoxy-2-{[(4-methoxy-3,5-dimethylpyrid-2-yl)methyl]sulph inyl}-1H-imidazo[4,5-b]pyridine (TU-199), an imidazopyridine derivative, on gastric acid secretion stimulated by histamine, carbachol and tetragastrin. We have also investigated the duration of the antisecretory effect of TU-199 using a measurement of intragastric pH for 24 h in gastric fistula dogs whose gastric acid secretion was stimulated by histamine. Single oral administration of TU-199 (0.1, 0.2 and 0.4mgkg(-1)) dose-dependently suppressed gastric acid secretion stimulated by histamine infusion. Oral treatment with TU-199 (0.2, 0.4 and 0.8 mg kg(-1)) also dose-dependently inhibited acid secretion induced by carbachol and tetragastrin. The inhibitory effect of TU-199 on stimulated gastric acid secretion was more potent than that of omeprazole, a well-known H+,K(+)-ATPase inhibitor in dogs. Repeated oral treatment with TU-199 at a dose of 0.2 mg kg(-1) once a day for seven days markedly suppressed histamine-stimulated gastric acid secretion in dogs. This inhibitory effect of TU-199 reached a maximum level after three or four doses and was more pronounced than that of omeprazole or lansoprazole. In gastric fistula dogs, the duration of intragastric pH-elevation by administration of TU-199 (0.3 mg kg(-1)) was much longer than that of omeprazole (0.6mgkg(-1)) or lansoprazole (0.9mgkg(-1)). The IC50 values (doses resulting in 50% inhibition) of TU-199, omeprazole and lansoprazole with regard to H+,K(+)-ATPase activity in dog gastric mucosal microsomes were 8.6, 8.8 and 9.9 microM, respectively. These results indicate that TU-199 inhibits gastric acid secretion via suppression of a H+,K(+)-ATPase activity. Our findings also suggest that TU-199 might have potent and long-lasting effects on gastric acid secretion.

• Authors: K Uchiyama, D Wakatsuki, B Kakinoki, Y Takeuchi, T Araki, Y Morinaka
• Journal: The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 51 Issue 4 Pg. 457-64 (Apr 1999) ISSN: 0022-3573 [Print] England
• PMID: 10385219 (Publication Type: Journal Article)

Chemical References

• 2-Pyridinylmethylsulfinylbenzimidazoles
• Analgesics, Non-Narcotic
• Anti-Ulcer Agents
• Enzyme Inhibitors
• Imidazoles
• Proton Pump Inhibitors
• Pyridines
• Lansoprazole
• Tetragastrin
• Histamine
• Carbachol
• H(+)-K(+)-Exchanging ATPase
• Omeprazole
• Tenatoprazole

Topics

• 2-Pyridinylmethylsulfinylbenzimidazoles
• Analgesics, Non-Narcotic (pharmacology)
• Animals
• Anti-Ulcer Agents (pharmacology)
• Carbachol (pharmacology)
• Dogs
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Female
• Gastric Acid (metabolism)
• Gastric Fistula
• Gastric Mucosa (drug effects, enzymology, metabolism)
• H(+)-K(+)-Exchanging ATPase (metabolism)
• Histamine (pharmacology)
• Hydrogen-Ion Concentration
• Imidazoles (pharmacology)
• Lansoprazole
• Male
• Microsomes (drug effects, enzymology)
• Omeprazole (analogs & derivatives, pharmacology)
• Proton Pump Inhibitors
• Pyridines (pharmacology)
• Stomach (drug effects, surgery)
• Tetragastrin (pharmacology)
• Time Factors