Pharmacological characterization of linaprazan glurate (X842), a novel potassium-competitive acid blocker, in vitro and in vivo
Abstract
Introduction 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 in vitro and in vivo to achieve a better pharmacological profile. Methods Pharmacokinetic profiling, hydrogen (H+)/potassium (K+)-ATPase inhibition, and gastric acid inhibition experiments were performed. Results 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–time curve of the two substances. Selective inhibition of the gastric H+/K+-ATPase and acid formation in vitro was observed. Linaprazan, X842, and vonoprazan selectively inhibited acid formation from gastric H+/K+-ATPase in a potassium-dependent manner. The inhibitory potency rank was vonoprazan > linaprazan > X842, with half-maximal inhibitory concentration (IC50) values of 17, 40, and 436 nM, respectively, showing that X842 is a very weak inhibitor of H+/K+-ATPase in vitro. 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+/K+-ATPase. Discussion X842 is a prodrug that exerts pharmacological effects both…
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