Correlation between acid secretion and proton pump activity during inhibition by the proton pump inhibitors omeprazole and pantoprazole

Omeprazole and pantoprazole are known to be irreversible, SH acting inhibit ors of gastric H+,K+-adenosine triphosphatase (H+,K+-ATPase). Both drugs co ncentration-dependently and pH-dependently inhibited K+ dependent e-nitroph enyl phosphatase (K+-pNPPase) activity in purified rabbit gastric microsome s. The potency of omeprazole was about three times that of pantoprazole in the pH ranges tested. Both drugs also inhibited acid secretion, as determin ed by [C-14]aminopyrine accumulation in isolated rabbit gastric glands, wit h the potency ratio being about 5 (omeprazole over that of pantoprazole). U nder conditions in which acid secretion was inhibited completely by the dru gs, the total K+-pNPPase activity in the digitonin-permeabilized glands was scarcely reduced, showing an apparent discrepancy between the acid secreti on and the proton pump activity. The isolated glands were stimulated with s ecretagogues for 30 min in the presence of the inhibitors, homogenized, and then separated into fractions in which K+-pNPPase activity was measured. O meprazole exclusively inhibited the activity in the low-speed fraction, whi ch was rich in the apical membranes, whereas pantoprazole did not inhibit a ctivity in any fraction. when the time of treatment with the inhibitors was increased up to 5 hr, the inhibition of the total K+-pNPPase activity in t he glands reached a plateau at an inhibition rate lower than 50% within 2 h r. This suggested that no continuous recycling of the proton pump was occur ring during stimulation. The inhibitory effect of both drugs on the permeab ilized gland preparation was less potent than that on the purified enzyme, especially at the higher pH, and it appeared to be partially reversibIe. Th e extent of the reduction in potency was more prominent for pantoprazole. I t is concluded that a lower amount of proton pump activity needs to be inhi bited by pantoprazole than by omeprazole to achieve the same extent of acid secretion inhibition. This appears to be due to the nature of pantoprazole , i.e.. the requirement of low FH for activation and the partial reversibil ity of the inhibition. (C) 1999 Elsevier Science Inc.