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

Matsukawa, Jun; Hori, Yasunobu; Nishida, Haruyuki; Kajino, Masahiro; Inatomi, Nobuhiro

doi:10.1016/j.bcp.2011.02.009

Cited by 96 publications

(84 citation statements)

References 31 publications

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“…Compared with LPZ, VPZ exhibits more potent and sustained acid-inhibitory effects, and induction of greater increases in gastric pH, consistent with the observation that VPZ accumulates to higher concentrations and is cleared at a slower rate from gastric glands (16,17). In addition, the intragastric pH following VPZ treatment (pH 5.2) has been identified to be significantly higher than that following esomeprazole treatment (pH 3.0) on day 1 of therapy (18).…”

Section: Eradication Rate % (N) -------------------------------------supporting

confidence: 53%

Second‑line triple therapy in failures with vonoprazan‑based triple therapy for eradication of Helicobacter pylori

et al. 2018

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Abstract. Gastric acid inhibition during treatment is important for the eradication of Helicobacter pylori (H. pylori) infection. A novel potassium-competitive acid blocker, vonoprazan (VPZ), has been demonstrated to achieve high eradication rates; however, the efficacy of second-line treatment in failures of VPZ-based triple therapy has not been well studied.The aim of the current study was to determine the efficacy of VPZ in a first-line regimen for H. pylori eradication, and the efficacy of a second-line regimen using metronidazole (MTZ) in failures with the first-line regimen. Of 580 subjects enrolled in the study, 524 patients completed first-line treatment (275 patients who received VPZ and 249 patients who received LPZ). First-line regimens consisted of a combination of clarithromycin (CAM) 200 or 400 mg twice a day, amoxicillin (AMPC) 750 mg twice a day, and either LPZ 30 mg or VPZ 20 mg twice a day, administered orally for 7 days. CAM and VPZ/LPZ were replaced with metronidazole (MTZ) 250 mg and rabeprazole 10 mg in the second-line regimens. The eradication of H. pylori was assessed by the H. pylori stool antigen test. The overall first-line eradication rate with VPZ was significantly higher than that with LPZ [91.0% (250/275) vs. 84.7% (211/249), respectively, P=0.030]. The dose of CAM (400 vs. 800 mg) did not affect the eradication rate in either the VPZ or LPZ regimens. The overall eradication rates of the second-line regimens with MTZ did not differ significantly between the VPZ-failure and LPZ-failure groups [87.0% (20/23) vs. 87.9% (29/33), respectively, P= 0.700]. Therefore, VPZ was significantly more effective than LPZ for first-line treatment. In patients with failure of first-line eradication therapy, successful results of second-line eradication therapy did not differ between the VPZ-and LPZ-failure groups. In conclusion, VPZ-based triple therapy should be recommended for eradication of H. pylori.

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Section: Eradication Rate % (N) -------------------------------------supporting

confidence: 53%

Second‑line triple therapy in failures with vonoprazan‑based triple therapy for eradication of Helicobacter pylori

et al. 2018

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“…On the other hand, TAK-438 showed a significant antisecretory effect with or without cimetidine pretreatment. TAK-438 was unaffected by ambient pH; it inhibited gastric H ϩ , K ϩ -ATPase activity and accumulated in cultured gastric glands in acidic and neutral conditions in vitro (Hori et al, 2010;Matsukawa et al, 2011). The results in this study indicate that inhibitory effect of TAK-438 on gastric acid secretion is also unaffected by the acid secretory state in vivo.…”

Section: Characteristics Of Antisecretory Effect Of Tak-438 801mentioning

confidence: 56%

“…Furthermore, PPIs cannot accumulate in the secretory canaliculi of the parietal cell under neutral conditions because the pK a values of PPIs range from 3.8 to 5.0. It has been reported that the uptake of PPIs into gastric glands was higher in acidic conditions when stimulated with an acid secretagogue than that in neutral conditions (Fellenius et al, 1982;Matsukawa et al, 2011). Thus, the effect of PPIs is altered by the gastric acid secretory state.…”

Section: Characteristics Of Antisecretory Effect Of Tak-438 801mentioning

confidence: 96%

“…The plasma t 1/2 of TAK-438 in dogs was 1.1 h, which is also short. TAK-438 may exert a potent and long-lasting antisecretory effect through high accumulation and long retention in the gastric glands because it strongly accumulates in cultured rabbit gastric glands and shows an inhibitory effect on forskolin-stimulated acid formation for more than 8 h after washout (Matsukawa et al, 2011). P-CABs are instantly protonated in an acidic environment; they bind to and inhibit H ϩ , K ϩ -ATPase in this protonated form (Andersson and Carlsson, 2005).…”

Section: Characteristics Of Antisecretory Effect Of Tak-438 801mentioning

confidence: 99%

“…High levels of TAK-438 accumulated in the resting and activated gastric glands in vitro. In addition, slow clearance of TAK-438 was observed, and the inhibitory effect of TAK-438 was maintained even after the glands were washed out (Matsukawa et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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A Study Comparing the Antisecretory Effect of TAK-438, a Novel Potassium-Competitive Acid Blocker, with Lansoprazole in Animals

Hori¹,

Matsukawa²,

Takeuchi³

et al. 2011

J Pharmacol Exp Ther

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136

108

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Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related diseases. However, several medical needs such as suppression of night-time acid secretion and rapid symptom relief remain unmet. In this study, we investigated the effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-Nmethylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker, on acid secretion in rats and dogs under various conditions, in comparison with the PPI, to characterize the antisecretory action of TAK-438. TAK-438 showed a more potent and longer-lasting inhibitory effect than lansoprazole on the histamine-stimulated gastric acid secretion in rats and dogs. A pharmacokinetic study in rats showed that TAK-438 accumulated and was retained in the gastric tissue for more than 24 h, unlike that in the plasma. TAK-438 showed significant antisecretory activity with or without cimetidine pretreatment, in contrast to lansoprazole, which did not show antisecretory activity after cimetidine pretreatment in rats. TAK-438 increased the pH of the gastric perfusate to 5.7 in an unstimulated condition, and this effect was maintained in the presence of subsequent histamine stimulation. On the other hand, lansoprazole also increased the pH in an unstimulated condition, but this effect diminished after histamine stimulation. These results indicated that TAK-438 exerted a more potent and longer-lasting antisecretory effect than lansoprazole through high accumulation and slow clearance from the gastric tissue. In addition, TAK-438 was unaffected by the gastric secretory state, unlike PPIs. Therefore, TAK-438 can provide a novel mechanism of action to improve the present PPI-based treatment of acid-related diseases.

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The Effect of Food on the Pharmacokinetics of the Potassium‐Competitive Acid Blocker Vonoprazan

Mulford¹,

Leifke²,

Hibberd³

et al. 2021

Clinical Pharm in Drug Dev

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Herein,we report a food-effect study of vonoprazan,an oral potassium-competitive acid blocker.In a phase 1,randomized, open-label, crossover study, healthy subjects received a single 20-mg dose of vonoprazan either following an overnight fast or 30 minutes after a high-fat breakfast. Plasma vonoprazan levels were determined at 0 hour and at 17 subsequent assessment points up to 48 hours after dosing. After a 5-day washout, subjects received a second 20-mg vonoprazan dose in the alternative fed/fasted state (identical process repeated). Twenty-four subjects completed the study. Vonoprazan exposure was not meaningfully affected by food. Geometric mean ratios for maximum concentration, area under the concentration-time curve from time 0 to 24 hours, and area under the plasma concentration-time curve extrapolated to infinity obtained under fed and fasting conditions were 1.05 (90% confidence interval, 0.98-1.12), 1.13 (1.09-1.18), and 1.15 (1.11-1.19), respectively. Four subjects experienced 6 adverse events that were all mild and considered unrelated to the study drug. Vonoprazan can be administered without regard to food intake.

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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

Cited by 96 publications

References 31 publications

Second‑line triple therapy in failures with vonoprazan‑based triple therapy for eradication of Helicobacter pylori

Second‑line triple therapy in failures with vonoprazan‑based triple therapy for eradication of Helicobacter pylori

A Study Comparing the Antisecretory Effect of TAK-438, a Novel Potassium-Competitive Acid Blocker, with Lansoprazole in Animals

The Effect of Food on the Pharmacokinetics of the Potassium‐Competitive Acid Blocker Vonoprazan

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