RT Journal Article
SR Electronic
T1 A Turnover Model of Irreversible Inhibition of Gastric Acid Secretion by Omeprazole in the Dog
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 662
OP 669
VO 295
IS 2
A1 Angela Äbelö
A1 Ulf G. Eriksson
A1 Mats O. Karlsson
A1 Håkan Larsson
A1 Johan Gabrielsson
YR 2000
UL http://jpet.aspetjournals.org/content/295/2/662.abstract
AB 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 (kome) 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 (kout) was 0.013 h−1 and the corresponding half-life of inhibition of acid secretory capacity was 54 h. The potency, calculated as koutover kome, 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. The American Society for Pharmacology and Experimental Therapeutics