Proton pump inhibitors (PPIs) were initially believed to block acid secretion permanently. Evidence that acid secretion returned after administration of the compounds led to investigations of the mechanism of this phenomenon. Data showing that, after omeprazole administration, acid secretion returned in less time than the half-life of the pump suggested that more than only new pump synthesis may play a role in acid recovery. In contrast, experiments with pantoprazole revealed a much longer time to the return of acid secretion than that seen with omeprazole, similar to that predicted from dependence on pump protein turnover. These data suggested that differences in the binding sites of the agents could explain differences in the time to acid return and shed light on the mechanisms. While omeprazole binds at cysteines 813 and 892, only cysteine 813 is involved in its inhibitory activity. Pantoprazole also binds at cysteine 813, but additionally at cysteine 822. Both of these sites are located in the proton transport pathway, though cysteine 822 is found deeper in the membrane domain than cysteine 813. Experiments in vitro and in vivo have shown that the reducing agent glutathione reverses the acid-inhibitory activity of omeprazole to a much greater degree than the activity of pantoprazole, most likely because glutathione cannot access cysteine 822. Thus, while the omeprazole-pump binding can be more easily reversed, pantoprazole-induced acid inhibition is overcome only by de novo pump synthesis. Clinically, this may lead to a longer duration of action and therapeutic advantages for pantoprazole. This has also been demonstrated in an analysis comparing pantoprazole to both omeprazoles, with pantoprazole showing superior relief of nighttime heartburn in patients with GERD.
(c) 2004 Prous Science