Vol. 295, Issue 2, 662-669, November 2000

A Turnover Model of Irreversible Inhibition of Gastric Acid Secretion by Omeprazole in the Dog

Angela Äbelö, Ulf G. Eriksson, Mats O. Karlsson, Håkan Larsson and Johan Gabrielsson

Drug Metabolism and Pharmacokinetics & Bioanalytical Chemistry (A.Ä.), Experimental Medicine (U.G.E.), and Gastrointestinal Pharmacology (H.L.), AstraZeneca R&D Mölndal, Mölndal, Sweden; Department of Pharmacy, Division of Biopharmaceutics and Pharmacokinetics, Biomedical Center, Uppsala University, Uppsala, Sweden (M.O.K.); and Drug Metabolism and Pharmacokinetics, AstraZeneca R&D, Södertälje, Sweden (J.G.)

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 h¹ and the corresponding half-life of inhibition 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, 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.