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
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
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DOI：
10.1016/j.bcp.2011.02.009
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发表时间：
2011-05-01
影响因子：
5.8
通讯作者：
Inatomi, Nobuhiro
中科院分区：
文献类型：
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作者：
Matsukawa, Jun;Hori, Yasunobu;Inatomi, Nobuhiro
TAK-438是一种新型钾竞争性酸阻滞剂（P-CAB）型抗分泌剂，可可逆性抑制胃H+，K+-ATP酶。之前，我们表明TAK-438在体内抑制酸分泌方面的疗效上级兰索拉唑（一种质子泵抑制剂）。在这项研究中，我们研究了两种药物的作用模式的差异，使用原代培养的兔胃腺。TAK-438和兰索拉唑抑制急性分离的胃腺中的胃酸形成（IC 50值分别为0.30和0.76 μ M）。在与TAK-438预孵育的培养胃腺中，对毛喉素刺激的酸形成的抑制作用在孵育期间增强，而兰索拉唑的抑制作用不受孵育时间的影响。接下来，我们评价了将胃腺与TAK-438和兰索拉唑孵育2 h后洗脱的TAK-438和兰索拉唑作用持续时间。即使在药物洗脱后8小时，较高浓度的TAK-438也可抑制酸形成，但兰索拉唑的抑制作用在洗脱后立即消失。此外，只有少量的[C-14]兰索拉唑在静息腺体中蓄积，用1 μ M毛喉素处理可增强这种蓄积。相比之下，在静息和毛喉素处理的腺体中均蓄积了高水平的[C-14] TAK-438。此外，2小时预孵育后洗脱证明[C-14] TAK-438从腺体中清除缓慢。这些结果表明，由于TAK-438的高蓄积和从胃腺中的缓慢清除，TAK-438比兰索拉唑发挥更长和更强效的抗分泌作用。(C)2011 Elsevier Inc. All rights reserved.
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 (IC50 values, 0.30 and 0.76 mu M, 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 [C-14] lansoprazole accumulated in resting glands, and this accumulation was enhanced by treatment with 1 mu M of forskolin. In contrast, high levels of [C-14] TAK-438 accumulated in both resting and forskolin-treated glands. Furthermore, a 2-h preincubation followed by washout demonstrated a slow clearance of [C-14] 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. (C) 2011 Elsevier Inc. All rights reserved.