Frontiers in pharmacology · 2025
Pharmacological characterization of linaprazan glurate (X842), a novel potassium-competitive acid blocker, in vitro and in vivo.
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Lu Ming, Cui Yi, Li Nailin, He Yan, Zhou Ling, Xiu Jin, Hu Pingsheng
Аннотация
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 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.
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 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.