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Biochim Biophys Acta. 1984 Dec 19;778(3):549-58.

Evidence for acid-induced transformation of omeprazole into an active inhibitor of (H+ + K+)-ATPase within the parietal cell.

Abstract

The chemical reactions of omeprazole, leading to inhibition of gastric acid secretion, were investigated. In acid buffer solutions, omeprazole was found to be labile, whereas at physiological pH it was stable (t1/2 greater than 17 h at pH 7.4). The stability of omeprazole was also studied in isolated, acid producing, gastric glands under conditions where acid formation was either stimulated or inhibited. The rate of transformation of omeprazole was high (t1/2 approximately 3 min) under stimulation. Inhibition of acid formation in the gland greatly retarded the decomposition of omeprazole (t1/2 approximately 73 min). The time-course for inhibition of acid formation by omeprazole was parallel to that for decomposition. The major product formed from omeprazole was the reduced form, H 168/22. The inhibitory action of omeprazole was shown to depend on acid-induced transformation, since no inhibition was obtained when omeprazole was incubated under neutral conditions, both in the isolated gastric mucosal- and the (H+ + K+)-ATPase preparations. Despite the fact that H 168/22 was the major product formed in the glandular preparation, it was found to be virtually inactive in both the glandular- and (H+ + K+)-ATPase preparations. Therefore, a model is proposed in which the inhibition of acid formation by omeprazole is mediated by a compound formed during the reduction of omeprazole to H 168/22 within the acid compartments of the parietal cell. Furthermore, mercaptanes, such as beta-mercaptoethanol, were found to prevent as well as reverse inhibition by omeprazole in both the glandular- and (H+ + K+)-ATPase preparations. This indicates that -SH groups are most likely involved in the chemical reactions leading to inhibition of acid secretion.

PMID:
6095911
[Indexed for MEDLINE]

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