Abstract

A turnover model for irreversible inhibition of gastric acid secretion by omeprazole in gastric fistula dogs was developed using data from studies with both short- and long-term measurement periods. In the short-term experiments, after stimulation of acid secretion with histamine, the dogs were infused i.v. with omeprazole and acid secretion was measured for 5 h. Dose and infusion times were varied to produce different concentration-time profiles and schedule dependence in the inhibitory effect of omeprazole was observed. In the long-term experiments, dogs were given single intraduodenal doses, 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 association rate constants (k_ome) for the covalent binding of omeprazole to H⁺,K⁺-ATPase were estimated to 11 and 3.0 l/μmol/h for the i.v. and intraduodenal experiments, respectively. The apparent turnover rate constant of the enzyme (k_out) was 0.013 h⁻¹ and the corresponding half-life of inhibition of acid secretory capacity was 54 h. The potency, calculated as k_outover k_ome, was 4.3 and 1.2 nM for the intraduodenal and i.v. doses, respectively. Allometric scaling of the model resulted in trustworthy predictions 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.