Home | My Profile | Contact Us
Research Trends Products  |   order gateway  |   author gateway  |   editor gateway  
Register | Forgot Password

Author Resources
 Author Gateway
 Article submission guidelines

Editor Resources
 Editor/Referee Gateway

 Regional Subscription Agents/Distributors
Current Topics in Pharmacology   Volumes    Volume 5 
The relationship between pH-selectivity, chirality, and efficacy of gastric proton pump inhibitors
Wolfgang Kromer
Pages: 45 - 69
Number of pages: 25
Current Topics in Pharmacology
Volume 5 

Copyright © 2000 Research Trends. All rights reserved


Gastric proton pump inhibitors (PPIs) are substituted benzimidazole prodrugs. They are converted by acid inside the canaliculus of the parietal cell into a cyclic sulfenamide that immediately reacts with SH-groups of the H+/K+ -ATPase in a covalent manner. Since only a fraction of parietal cells is in the acid-secreting state at any time of drug administration, the chemical activation half-life of PPIs at pH 1, relative to their serum elimination half- life, will determine their antisecretory effect. No relevant differences in this respect are detectable between the PPIs.

In order to avoid unwanted SH reactions in cells apart from the parietal cell, PPIs should be converted into their active principle as slowly as possible at pH values above 3. For example, pH values around 5 are encountered in lysosomes which are affected in their function both, in vitro and ex vivo, by omeprazole. This contrasts to the more pH-selective PPI pantoprazole. Rabeprazole is by far the least pH-selective PPI with a chemical activation half-life at pH 5 in the order of 0.1 h, compared to about 2 h at 37°C in the case of pantoprazole. Since all the PPIs have a similar serum elimination half-life of about 1h (with a wide variation between subjects from 0.5 to 2 h), rabeprazole is expected to be more liable to cause unwanted SH reactions. Actually, incidences of infectious and inflammatory adverse events between 2 and 5 % have been listed in the `Summary of Product Characteristics` of rabeprazole, compared to only 0.12 - 0.14 % found in clinical studies on pantoprazole. Although these data are derived from different clinical studies, this preliminary comparison between the two PPIs is at least in line with the notion of biologically relevant differences in pH-selectivities of PPIs.

As opposed to the prodrugs, the cyclic sulfenamides are achiral and no longer optically active. Consequently, the (S)-enantiomer of omeprazole (esomeprazole) is equieffective compared to the racemate, in terms of pharmacodynamics. Since esomeprazole displays a slightly longer serum elimination half-life than the (R)-enantiomer in extensive metabolizers, it has been claimed to be more effective than the racemate, on a mg basis. However, the racemate already contains 50 % of the (S)-enantiomer, and overall healing rates do not seem to support the above claim. Consequently, esomeprazole`s dose for acute healing has been raised from the original dose of 20 mg omeprazole racemate to that dose previously found to be optimal in the development of pantoprazole, namely 40 mg.

Buy this Article


Buy this article
Buy this volume
Subscribe to this title
Shopping Cart

Quick Links
Search Products
Browse in Alphabetical Order : Journals
Browse by Subject Classification : Journals

Ordering Information Ordering Information
Downloadable forms Downloadable Forms