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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.
MedLine Citation:
PMID:  21371447     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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 0.76μM, 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 2h followed by washout. Even 8h 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 [(14)C] lansoprazole accumulated in resting glands, and this accumulation was enhanced by treatment with 1μM of forskolin. In contrast, high levels of [(14)C] TAK-438 accumulated in both resting and forskolin-treated glands. Furthermore, a 2-h preincubation followed by washout demonstrated a slow clearance of [(14)C] 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.
Authors:
Jun Matsukawa; Yasunobu Hori; Haruyuki Nishida; Masahiro Kajino; Nobuhiro Inatomi
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-2-28
Journal Detail:
Title:  Biochemical pharmacology     Volume:  -     ISSN:  1873-2968     ISO Abbreviation:  -     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-3-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011. Published by Elsevier Inc.
Affiliation:
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan.
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