PANTOPRAZOLE - A NOVEL H+/K+-ATPASE INHIBITOR WITH AN IMPROVED PH STABILITY

The action of the H+/K+-ATPase inhibitors pantoprazole and omeprazole was compared in different in vitro test systems. In gastric membrane vesicles under conditions shown to result in acidification of the vesicle interior, pantoprazole and omeprazole inhibited H+/K+-ATPase activity with IC50 values of 6.8 and 2.4-mu-M, respectively. When intravesicular acidification was reduced by inclusion of imidazole (5 mM), a membrane permeable weak base, the inhibitory action of omeprazole was partially lost (IC50 30-mu-M) and that of pantoprazole almost completely lost. After incubation for 40 min with pumping membrane vesicles, a half-maximal reduction in intravesicular H+ concentration occurred at pantoprazole and omeprazole concentrations of 1.1 and 0.6-mu-M, respectively. Again, when the intravesicular H+ concentration was reduced by inclusion of imidazole (2.5 mM), pantoprazole (20 and 60-mu-M) did not reduce the remaining intravesicular proton concentration, whereas omeprazole (10 and 30-mu-M) did. Both drugs inhibited, with similar potency, papain activity at pH 3.0 and inactivated the enzyme in a similar time-dependent manner; at pH 5.0 omeprazole (IC50 17-mu-M) was more potent than pantoprazole (IC50 37-mu-M) and enzyme inhibition was faster than with pantoprazole. These results indicate that pantoprazole is a potent inhibitor of H+/K+-ATPase under highly acidic conditions and that it is more stable than omeprazole at a slightly acidic pH such as pH 5.0.