A comparative study on the modes of action of TAK-438, a novel potassium-competitive acid blocker, and lansoprazole in primary cultured rabbit gastric glands

• Published in: Biochemical pharmacology 2011-05, Vol.81 (9), p.1145-1151
• Main Authors: Matsukawa, Jun, Hori, Yasunobu, Nishida, Haruyuki, Kajino, Masahiro, Inatomi, Nobuhiro
• Format: Article
• Language: English
• Subjects: 2-Pyridinylmethylsulfinylbenzimidazoles - pharmacology; Animals; Anti-Ulcer Agents - pharmacology; Biological and medical sciences; Cells, Cultured; drugs; forskolin; gastric acid; Gastric glands; gastric mucosa; H +, K +-ATPase; H(+)-K(+)-Exchanging ATPase - metabolism; incubation period; Lansoprazole; mechanism of action; Medical sciences; P-CAB; Pharmacology. Drug treatments; Potassium - metabolism; proton pump; Proton Pump Inhibitors; Pyrroles - pharmacology; Rabbits; secretion; Stomach - cytology; Stomach - drug effects; Sulfonamides - pharmacology; TAK-438
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2011.02.009

TAK-438 is a novel potassium-competitive acid blocker (P-CAB) type antisecretory agent that reversibly inhibits gastric H +, K +-ATPase. Previously, we showed that TAK-438 has superior efficacy compared to lansoprazole, a proton pump inhibitor, in the inhibition of acid secretion in vivo. In this study, we investigated the differences in the mode of actions of the two drugs using primary cultured rabbit gastric glands. TAK-438 and lansoprazole inhibited gastric acid formation in acutely isolated gastric glands (IC 50 values, 0.30 and 0.76 μM, respectively). In cultured gastric glands that were preincubated with TAK-438, the inhibitory effect on forskolin-stimulated acid formation was augmented over the incubation period, whereas the inhibitory effect of lansoprazole was not affected by time of incubation. Next, we evaluated the durations of the actions of TAK-438 and lansoprazole after gastric glands were incubated with either drug for 2 h followed by washout. Even 8 h after the drug washout, TAK-438 at higher concentrations inhibited acid formation, but the inhibitory effect of lansoprazole disappeared immediately after washout. Additionally, only a small amount of [ 14C] lansoprazole accumulated in resting glands, and this accumulation was enhanced by treatment with 1 μM of forskolin. In contrast, high levels of [ 14C] TAK-438 accumulated in both resting and forskolin-treated glands. Furthermore, a 2-h preincubation followed by washout demonstrated a slow clearance of [ 14C] TAK-438 from the glands. These findings suggest that TAK-438 exerts a longer and more potent antisecretory effect than lansoprazole as a result of its high accumulation and slow clearance from the gastric glands.