title: Animal pharmacology of reversible antagonism of the gastric acid pump, compared to standard antisecretory principles.
abstract: To define the basic antisecretory profile of a potassium-competitive antagonism of the gastric acid pump relative to other classes of acid-inhibitory drugs, they were compared to each other against all three major stimuli of acid secretion. Pumaprazole is an imidazo-pyridine derivative that was used in this investigation as an example of reversibly binding acid pump antagonists (APAs). It differs from covalently binding proton pump inhibitors (PPIs), such as omeprazole, both with respect to chemical structure and mode of interaction with the gastric H(+)/K(+)-ATPase (i.e., the acid or proton pump). The present data show that a single dose of pumaprazole is able to elevate intragastric pH in the dog with gastric fistula under pentagastrin or carbachol stimulation from pH 1 to about pH 7 while still displaying a dose-dependent, well-controlable duration of action of a few hours. Ranitidine at the same oral dose also shows a short duration of action, but combined with a far lower efficacy. By contrast, a single oral dose of the PPI omeprazole elevates intragastric pH for a longer time period, but this pH elevation is far lower compared to that of the APA. Regarding the less stringent parameter of inhibition of total acid output in the Heidenhain pouch dog, the modified Shay rat or the Ghosh-Schild rat, pumaprazole is, overall, slightly more efficacious than ranitidine. The M(1)-muscarinic antagonist pirenzepine is ineffective (against histamine stimulation) or far less effective than pumaprazole (against pentagastrin-stimulation), but as effective as pumaprazole against carbachol stimulation in the Ghosh-Schild rat. Basal acid output in the same model is more effectively inhibited by pumaprazole than by ranitidine. In conclusion, our data demonstrate the exceptional ability of a reversibly binding APA to elevate intragastric pH up to neutrality even upon a first administration while still displaying a limited, dose-dependent duration of action.
authors.affiliation: Department of Pharmacology, Byk Gulden, Constance, Germany. Wolfgang.Kromer@byk.de
authors.forename: W
authors.initials: W
authors.lastname: Kromer
authors.forename: S
authors.initials: S
authors.lastname: Postius
authors.forename: R
authors.initials: R
authors.lastname: Riedel
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010295:Parietal Cells, Gastric / Q000187:drug effects* / Q000378:metabolism; D010890:Pirenzepine / Q000494:pharmacology; D054328:Proton Pump Inhibitors; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001562:Benzimidazoles; D006635:Histamine H2 Antagonists; D018727:Muscarinic Antagonists; D054328:Proton Pump Inhibitors; D010890:Pirenzepine; D011899:Ranitidine