The Long-lasting Effect of TU-199, a Novel H+,K+-ATPase Inhibitor, on Gastric Acid Secretion in Dogs

Abstract

Abstract We have used Heidenhain-pouch dogs to investigate the effects of (±)-5-methoxy-2-{[(4-methoxy-3,5-dimethylpyrid-2-yl)methyl]sulphinyl}-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 0.4 mg kg−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 (0.6 mg kg−1) or lansoprazole (0.9 mg kg−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 μM, 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.