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Commentaires:
PPIs differ in their rate of activation, depending on the reactivity of the molecule and the environmental pH.
As mentioned, PPIs are converted from prodrugs to active sulfenamide moieties in an acidic environment. The sulfenamide moieties, in turn, covalently react with the cysteine (-SH) groups on the extracytoplasmic face of the H+,K+-ATPase. (1)
With its higher pKa, more rabeprazole is protonated relative to other PPIs at higher pH levels. In vitro studies of rabeprazole have shown its comparatively faster inhibition of proton pump function.
As shown on the slide, rabeprazole is rapidly activated at pH 1.2 – within 1.3 minutes. Lansoprazole and omeprazole are similarly activated in about 2 minutes. Pantoprazole has a much longer time to activation – about 4.6 minutes.
Compared with these other PPIs, the time to activation of rabeprazole, even at pH 5.1, is very rapid – about 7.1 minutes. Omeprazole and lansoprazole are activated within 1.4 and 1.5 hours, respectively, at this pH. Because pantoprazole is more acid stabl
The comparatively early antisecretory effects of rabeprazole reflect its rapid activation at the standard pH of the stomach. (2)
Kromer W, Kruger U, Huber R, Hartmann M, Steinijans VW. Differences in pH-dependent activation rates of substituted benzimidazoles and biological in vitro correlates. Pharmacology. 1998;56:57-70.
Besancon M, Simon A, Sachs G, Shin JM. Sites of reaction of the gastric H,K-ATPase with extracytoplasmic thiol reagents. J Biol Chem. 1997;272:22438-22446.
