The long-lasting effect of TU-199, a novel H+, K(+)-ATPase inhibitor, on gastric acid secretion in dogs.
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.
Uchiyama
K
K
Medicinal Research Group II, Kazusa Research Laboratories, Tokyo Tanabe Company Limited, Chiba, Japan. k-uchiy@kazusa.tokyo-tanabe.co.jp
Wakatsuki
D
D
Kakinoki
B
B
Takeuchi
Y
Y
Araki
T
T
Morinaka
Y
Y
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D005747:Gastric Fistula; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000494:pharmacology*; D064747:Lansoprazole; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D009853:Omeprazole / Q000031:analogs & derivatives / Q000494:pharmacology; D054328:Proton Pump Inhibitors; D011725:Pyridines / Q000494:pharmacology*; D013270:Stomach / Q000187:drug effects / Q000601:surgery; D013758:Tetragastrin / Q000494:pharmacology; D013997:Time Factors
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D018712:Analgesics, Non-Narcotic; D000897:Anti-Ulcer Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D054328:Proton Pump Inhibitors; D011725:Pyridines; D064747:Lansoprazole; D013758:Tetragastrin; D006632:Histamine; D002217:Carbachol; D017506:H(+)-K(+)-Exchanging ATPase; D009853:Omeprazole; C119998:Tenatoprazole