A turnover model of irreversible inhibition of gastric acid secretion by omeprazole in the dog

A turnover model for irreversible inhibition of gastric acid secretion by o meprazole in gastric fistula dogs was developed using data from studies wit h both short- and long-term measurement periods. In the short- term experim ents, after stimulation of acid secretion with histamine, the dogs were inf used i.v. with omeprazole and acid secretion was measured for 5 h. Dose and infusion times were varied to produce different concentration-time profile s and schedule dependence in the inhibitory effect of omeprazole was observ ed. In the long-term experiments, dogs were given single intraduodenal dose s, which inhibited the acid secretion for several days. Combining the short - term and long-term data allowed the observation of a biphasic recovery of acid secretion that was described by the turnover model. Second order asso ciation rate constants (k(ome)) for the covalent binding of omeprazole to H +,K+-ATPase were estimated to 11 and 3.0 l/mu mol/h for the i.v. and intrad uodenal experiments, respectively. The apparent turnover rate constant of t he enzyme (k(out)) was 0.013 h(-1) and the corresponding half-life of inhib ition of acid secretory capacity was 54 h. The potency, calculated as k(out ) over k(ome), was 4.3 and 1.2 nM for the intraduodenal and i.v. doses, res pectively. Allometric scaling of the model resulted in trustworthy predicti ons for observations previously done in humans. The model predicted a good correlation between maximal inhibitory effect and exposure (area under the plasma concentration curve). The time dependence in this relation was also predicted by the model.