{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T14:08:37Z","timestamp":1793196517844,"version":"4.5.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T00:00:00Z","timestamp":1757030400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006321","name":"National Institutes of Natural Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004001","name":"Guizhou Provincial Science and Technology Department","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009619","name":"Science and Technology Bureau, Guiyang Municipal Government","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The aim of this study is to characterize the pharmacology of linaprazan glurate (X842), an ethyl ester prodrug of linaprazan (a novel potassium-competitive acid blocker), in animal species <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> to achieve a better pharmacological profile.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Pharmacokinetic profiling, hydrogen (H<jats:sup>+<\/jats:sup>)\/potassium (K<jats:sup>+<\/jats:sup>)-ATPase inhibition, and gastric acid inhibition experiments were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>X842 was rapidly absorbed with a very low plasma concentration. X842 was rapidly transformed by enzymatic cleavage into its active metabolite, linaprazan, as shown by the half-life, maximum concentration, and area under the concentration\u2013time curve of the two substances. Selective inhibition of the gastric H<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>-ATPase and acid formation <jats:italic>in vitro<\/jats:italic> was observed. Linaprazan, X842, and vonoprazan selectively inhibited acid formation from gastric H<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>-ATPase in a potassium-dependent manner. The inhibitory potency rank was vonoprazan &amp;gt; linaprazan &amp;gt; X842, with half-maximal inhibitory concentration (IC<jats:sub>50<\/jats:sub>) values of 17, 40, and 436\u00a0nM, respectively, showing that X842 is a very weak inhibitor of H<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>-ATPase <jats:italic>in vitro<\/jats:italic>. In a pylorus-ligated rat model, X842 potently inhibited gastric acid secretion in a dose-dependent manner with a long duration of action, highlighting the two stages of pharmacokinetics that give the compound both its fast onset and its long-lasting duration of action on H<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>-ATPase.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>X842 is a prodrug that exerts pharmacological effects both independently and through its metabolized active compound linaprazan, with both a fast onset and a long duration of action. X842 could be a potential drug candidate worthy of further clinical study.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1636523","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T04:14:29Z","timestamp":1757045669000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacological characterization of linaprazan glurate (X842), a novel potassium-competitive acid blocker, in vitro and in vivo"],"prefix":"10.3389","volume":"16","author":[{"given":"Ming","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nailin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Xiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingsheng","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1002\/bdd.315","article-title":"The bioavailability and pharmacokinetics of glucosamine hydrochloride and low molecular weight chondroitin sulfate after single and multiple doses to beagle dogs","volume":"23","author":"Adebowale","year":"2002","journal-title":"Biopharm. Drug Dispos."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e65141","DOI":"10.7759\/cureus.65141","article-title":"Comparison of potassium-competitive acid blockers and proton pump inhibitors in patients with gastroesophageal reflux disease: a systematic review and meta-analysis of randomized controlled trials","volume":"16","author":"Agago","year":"2024","journal-title":"Cureus"},{"key":"B3","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/j.pharmthera.2005.05.005","article-title":"Potassium-competitive acid blockade: a new therapeutic strategy in acid-related diseases","volume":"108","author":"Andersson","year":"2005","journal-title":"Pharmacol. Ther."},{"key":"B4","doi-asserted-by":"publisher","first-page":"4446","DOI":"10.1021\/jm300318t","article-title":"Discovery of a novel pyrrole derivative 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate (TAK-438) as a potassium-competitive acid blocker (P-CAB)","volume":"55","author":"Arikawa","year":"2012","journal-title":"J. Med. Chem."},{"key":"B5","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1111\/apt.13331","article-title":"Randomised clinical trial: a dose-ranging study of vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the treatment of erosive oesophagitis","volume":"42","author":"Ashida","year":"2015","journal-title":"Aliment. Pharmacol. Ther."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2769","DOI":"10.1194\/jlr.D700010-JLR200","article-title":"A rapid fluorescence assay for sphingosine-1-phosphate lyase enzyme activity","volume":"48","author":"Bandhuvula","year":"2007","journal-title":"J. Lipid Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"2356","DOI":"10.3390\/molecules26082356","article-title":"Good-practice non-radioactive assays of inorganic pyrophosphatase activities","volume":"26","author":"Baykov","year":"2021","journal-title":"Molecules"},{"key":"B8","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1007\/s40265-024-02057-w","article-title":"Zastaprazan: first approval","volume":"84","author":"Blair","year":"2024","journal-title":"Drugs"},{"key":"B9","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1111\/j.1572-0241.2007.01544.x","article-title":"A randomized, comparative trial of a potassium-competitive acid blocker (AZD0865) and esomeprazole for the treatment of patients with nonerosive reflux disease","volume":"103","author":"Dent","year":"2008","journal-title":"Am. J. Gastroenterol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.2165\/00003495-200767110-00001","article-title":"Proton-pump inhibitor therapy in patients with gastro-oesophageal reflux disease: putative mechanisms of failure","volume":"67","author":"Fass","year":"2007","journal-title":"Drugs"},{"key":"B11","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.ab.2010.10.025","article-title":"An improved malachite green assay of phosphate: mechanism and application","volume":"409","author":"Feng","year":"2011","journal-title":"Anal. Biochem."},{"key":"B12","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1007\/s40265-015-0368-z","article-title":"Vonoprazan: first global approval","volume":"75","author":"Garnock-jones","year":"2015","journal-title":"Drugs"},{"key":"B13","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/j.bcp.2006.09.020","article-title":"Mechanism of action of AZD0865, a K+-competitive inhibitor of gastric H+,K+-ATPase","volume":"73","author":"Gedda","year":"2007","journal-title":"Biochem. Pharmacol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"S8","DOI":"10.14309\/00000434-200410001-00022","article-title":"AZD0865, A potassium-competitive acid blocker (P-CAB), has a long duration of effect in the rat:22","volume":"99","author":"Holstein","year":"2004","journal-title":"Am. J. Gastroenterology"},{"key":"B15","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1124\/jpet.110.170274","article-title":"1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel and potent potassium-competitive acid blocker for the treatment of acid-related diseases","volume":"335","author":"Hori","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B16","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1124\/jpet.111.179556","article-title":"A study comparing the antisecretory effect of TAK-438, a novel potassium-competitive acid blocker, with lansoprazole in animals","volume":"337","author":"Hori","year":"2011","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B17","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1111\/jgh.13233","article-title":"Rapid metabolizer genotype of CYP2C19 is a risk factor of being refractory to proton pump inhibitor therapy for reflux esophagitis","volume":"31","author":"Ichikawa","year":"2016","journal-title":"J. Gastroenterol. Hepato"},{"key":"B18","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.pharmthera.2016.08.001","article-title":"Potassium-competitive acid blockers: advanced therapeutic option for acid-related diseases","volume":"168","author":"Inatomi","year":"2016","journal-title":"Pharmacol. Ther."},{"key":"B19","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1080\/02652048.2018.1515997","article-title":"Novel revaprazan-loaded gelatin microsphere with enhanced drug solubility and oral bioavailability","volume":"35","author":"Kim","year":"2018","journal-title":"J. Microencapsul."},{"key":"B20","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1177\/1087057111421004","article-title":"High-throughput screening of potassium-competitive acid blockers","volume":"17","author":"Kondo","year":"2012","journal-title":"J. Biomol. Screen"},{"key":"B21","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1038\/s41401-019-0353-2","article-title":"Physiologically based pharmacokinetic-pharmacodynamic modeling for prediction of vonoprazan pharmacokinetics and its inhibition on gastric acid secretion following intravenous\/oral administration to rats, dogs and humans","volume":"41","author":"Kong","year":"2020","journal-title":"Acta Pharmacol. Sin."},{"key":"B22","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1111\/j.2042-7158.1998.tb00696.x","article-title":"Use of one cannula for both blood sampling and drug administration: a potential cause of overestimation of drug concentration","volume":"4","author":"Kotegawa","year":"1998","journal-title":"Pharm. Pharmacol. Commun."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1228","DOI":"10.1124\/jpet.102.035972","article-title":"In vitro, pharmacokinetic, and pharmacodynamic interactions of ketoconazole and midazolam in the rat","volume":"302","author":"Kotegawa","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B24","doi-asserted-by":"publisher","first-page":"3608","DOI":"10.3748\/wjg.v28.i28.3608","article-title":"Potassium-competitive acid blockers and gastroesophageal reflux disease","volume":"28","author":"Leowattana","year":"2022","journal-title":"World J. Gastroenterol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/med.2610100102","article-title":"Omeprazole: the first proton pump inhibitor","volume":"10","author":"Lindberg","year":"1990","journal-title":"Med. Res. Rev."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1724","DOI":"10.1136\/gutjnl-2022-327745","article-title":"Management of Helicobacter pylori infection: the maastricht VI\/Florence consensus report","volume":"71","author":"Malfertheiner","year":"2022","journal-title":"Gut"},{"key":"B27","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1517\/17425255.2.6.875","article-title":"Species differences between mouse, rat, dog, monkey and human CYP-Mediated drug metabolism, inhibition and induction","volume":"2","author":"Martignoni","year":"2006","journal-title":"Expert Opin. drug metabolism and Toxicol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1038\/nrd1010","article-title":"A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole","volume":"2","author":"Olbe","year":"2003","journal-title":"Nat. Rev. Drug Discov."},{"key":"B29","doi-asserted-by":"publisher","first-page":"334","DOI":"10.5056\/jnm18029","article-title":"Potent potassium-competitive acid blockers: a new era for the treatment of acid-related diseases","volume":"24","author":"Oshima","year":"2018","journal-title":"J. Neurogastroenterol. Motil."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.1007\/s12325-016-0345-2","article-title":"Characteristics of the novel potassium-competitive acid blocker vonoprazan fumarate (TAK-438)","volume":"33","author":"Otake","year":"2016","journal-title":"Adv. Ther."},{"key":"B31","doi-asserted-by":"publisher","first-page":"63","DOI":"10.4292\/wjgpt.v9.i7.63","article-title":"Potassium-competitive acid blockers-are they the next generation of proton pump inhibitors?","volume":"9","author":"Rawla","year":"2018","journal-title":"World J. Gastrointest. Pharmacol. Ther."},{"key":"B32","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1007\/s11894-024-00939-3","article-title":"Potassium-competitive acid blockers: current clinical use and future developments","volume":"26","author":"Scarpignato","year":"2024","journal-title":"Curr. Gastroenterol. Rep."},{"key":"B33","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1111\/apt.13493","article-title":"Corrigendum. The binding selectivity of vonoprazan (TAK-438) to the gastric H+,K+-ATPase","volume":"43","author":"Scott","year":"2016","journal-title":"Aliment. Pharmacol. Ther."},{"key":"B34","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1124\/jpet.111.185314","article-title":"Characterization of a novel potassium-competitive acid blocker of the gastric H,K-ATPase, 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamin e monofumarate (TAK-438)","volume":"339","author":"Shin","year":"2011","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B35","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1111\/j.1749-6632.1982.tb25741.x","article-title":"The (Na+ + K+)-ATPase: coupling of the reaction with ATP to the reaction with Na+ and K+","volume":"402","author":"Skou","year":"1982","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1016\/j.bmcl.2011.12.125","article-title":"Imidazopyridines as selective CYP3A4 inhibitors","volume":"22","author":"Song","year":"2012","journal-title":"Bioorg. and Med. Chem. Lett."},{"key":"B37","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1002\/rcm.1290060308","article-title":"Studies on the metabolism of omeprazole in the rat using liquid chromatography\/ionspray mass spectrometry and the isotope cluster technique with [34S] omeprazole","volume":"6","author":"Weidof","year":"1992","journal-title":"Rapid Commun. mass Spectrom."},{"key":"B38","first-page":"693","article-title":"Potassium-competitive acid blockers: present and potential utility in the armamentarium for acid peptic disorders","volume":"18","author":"Wong","year":"2022","journal-title":"Gastroenterol. Hepatol. (N Y)."},{"key":"B39","doi-asserted-by":"publisher","first-page":"116012","DOI":"10.1016\/j.jpba.2024.116012","article-title":"Absorption, distribution, metabolism and excretion of linaprazan glurate in rats","volume":"242","author":"Zhang","year":"2024","journal-title":"J. Pharm. Biomed. Anal."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1636523\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T04:14:30Z","timestamp":1757045670000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1636523\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,5]]},"references-count":39,"alternative-id":["10.3389\/fphar.2025.1636523"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1636523","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,5]]},"article-number":"1636523"}}