Abstract
Tegoprazan [(S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide], a potassium-competitive acid blocker (P-CAB), is a novel potent and highly selective inhibitor of gastric H+/K+-ATPase. Tegoprazan inhibited porcine, canine, and human H+/K+-ATPases in vitro with IC50 values ranging from 0.29 to 0.52 μM, while that for canine kidney Na+/K+-ATPase was more than 100 μM. A kinetic analysis revealed that tegoprazan inhibited H+/K+-ATPase in a potassium-competitive manner and the binding was reversible. Oral single administrations of tegoprazan ranging from 0.3 to 30 mg/kg in dogs were well absorbed into the blood stream and distributed in gastric tissue/fluid higher than in plasma. Tegoprazan potently inhibited histamine-induced gastric acid secretion in dogs, and a complete inhibition was observed at 1.0 mg/kg starting from 1 hour after administration. Moreover, an oral administration of tegoprazan at 1 and 3 mg/kg reversed the pentagastrin-induced acidified gastric pH to the neutral range. Interestingly, 3 mg/kg tegoprazan immediately evoked a gastric phase III contraction of the migrating motor complex in pentagastrin-treated dogs and similar effects was observed with the other P-CAB, vonoprazan. Tegoprazan is the novel P-CAB that may provide a new option for the therapy of gastric acid-related and motility-impaired diseases.
Highlights
Acid-related gastrointestinal diseases such as gastroesophageal reflux disease, nonerosive reflux disease, gastric ulcers, and nonsteroidal anti-inflammatory drug–associated ulcers are the most common diseases among gastrointestinal disorder
Drug therapies starting from histamine receptor 2 blockers and following proton pump inhibitors (PPIs) demonstrate the efficacy of the inhibition of gastric acid secretion for the treatment of acid-related diseases, and those new drugs dramatically improved the quality of life of patients
Since evidence has indicated a relationship between gastric acid inhibition and disorder in phase III migrating motor complex (MMC), we evaluated the pharmacological effects of tegoprazan to evoke gastric phase III MMC contractions in the pentagastrin-treated dog model (Parkman et al, 1998)
Summary
Acid-related gastrointestinal diseases such as gastroesophageal reflux disease, nonerosive reflux disease, gastric ulcers, and nonsteroidal anti-inflammatory drug–associated ulcers are the most common diseases among gastrointestinal disorder. Drug therapies starting from histamine receptor 2 blockers and following proton pump inhibitors (PPIs) demonstrate the efficacy of the inhibition of gastric acid secretion for the treatment of acid-related diseases, and those new drugs dramatically improved the quality of life of patients. The common properties of the currently available PPIs (e.g., PPIs require chemical transformation to active form and simultaneous activation of H1/K1-ATPase on the parietal cell membrane for inhibition of acid secretion, bind to the target molecule irreversibly, and eliminate from plasma rapidly) often cause insufficient gastric pH control that may result in therapeutic failure (Hunt, 2012; Inatomi et al, 2016).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Journal of Pharmacology and Experimental Therapeutics
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
