INHIBITION OF GASTRIC K+/H+-ATPASE BY ACID-ACTIVATED 2-((2-PYRIDYLMETHYL)SULPHINYL)BENZIMIDAZOLE PRODUCTS

The inhibitory effects of timoprazole- and omeprazole-derived metabolites were studied in different in vitro test systems in order to characterize the metabolites of substituted benzimidazoles originating from acid activation. Acidification of timoprazole and omeprazole and omeprazole to pH 1.0 markedly increased the inhibitory potency on gastric K+/H+-ATPase. The timoprazole-derived tetracyclic thiol and radical were found to be equally or more potent on the K+/H+-ATPase than the mother compounds dissolved at pH 1.0. Kinetic studies with omeprazole sulphide revealed a competitive inhibition of the K+/H+-ATPase with respect to K+. The mercaptan dithiothreitol reversed the inhibitory effect of omeprazole, acidified timoprazole and the timoprazole-derived radical in the parietal cell and K+/H+-ATPase preparation. In contrast, the inhibitory effect of omeprazole sulphide and the timoprazole-derived thiol could not be reversed by dithiothreitol. Wash-out experiments indicated that acidified timoprazole and the tetracyclic compounds interact irreversibly with the K+/H+-ATPase, which contrasts with the properties of timoprazole in the parietal cell preparation. It is concluded from these data that neither the tetracyclic compounds nor the sulphide act as the ''active principle'' of substituted benzimidazoles in the parietal cell preparation.