Submitted on March 16, 2006
Accepted on May 31, 2006
Characteristics of the K+-competitive H+,K+-ATPase Inhibitor
AZD0865 in isolated rat gastric glands
Philipp Kirchhoff1, Kjell Andersson2, Thenral Socrates1, Shafik M Sidani1, Ortrud Kosiek1, and John P Geibel1*
1 Dept of Surgery, Yale University, New Haven, Connecticut, United States
2 AstraZeneca, Molndal, Sweden
* To whom correspondence should be addressed. E-mail: john.geibel{at}yale.edu.
The gastric H+,K+-ATPase of the parietal cell is responsible for acid secretion in the stomach, and is the main target in the pharmacological treatment of acid related diseases. Omeprazole and other benzimidazole drugs although having delayed efficacy if taken orally have high success rates in the treatment of peptic ulcer disease. Potassium Competitive Acid Blockers (P-CAB) compete with K+ for binding to the H+,K+-ATPase and thereby they inhibit acid secretion. In this study the in vitro properties of AZD0865, a reversible H+,K+-ATPase inhibitor of gastric acid secretion is described.
We used a digital-imaging system and the pH sensitive dye BCECF to observe proton efflux from hand dissected gastric glands. Glands were stimulated with histamine (100µmol) and exposed to a bicarbonate and Na+ free perfusate to induce an acid load. H+,K+-ATPase inhibition was determined by calculating pHi recovery (dpH/dT) in the presence of omeprazole (10-200µmol) or AZD0865 (0.01-100µmol). The efficacies of both drugs were compared.
Our data show that acid secretion is inhibited by both the proton pump inhibitor omeprazole and the P-CAB AZD0865. Complete inhibition of acid secretion by AZD0865 had a rapid onset of activation, was reversible, and occurred at a 100 fold lower dose than omeprazole (1µmol AZD0865 versus 100µmol omeprazole).
This study demonstrates that AZD0865 is a potent, fast acting inhibitor of gastric acid secretion, effective at lower concentrations than drugs of the benzimidazole class. Therefore this data strongly suggest that AZD0865 has great potential as a fast acting, low dose inhibitor of acid secretion.
