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A turnover model of irreversible inhibition of gastric acid secretion by omeprazole in the dog
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy. (Farmakometri)
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2000 (English)In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 295, no 2, 662-669 p.Article in journal (Refereed) Published
Abstract [en]

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/micromol/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(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.

Place, publisher, year, edition, pages
2000. Vol. 295, no 2, 662-669 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-91078PubMedID: 11046103OAI: oai:DiVA.org:uu-91078DiVA: diva2:163668
Available from: 2003-11-20 Created: 2003-11-20 Last updated: 2011-11-30Bibliographically approved
In thesis
1. Pharmacodynamic Modelling of Irreversible and Reversible Gastric Proton Pump Inhibitors
Open this publication in new window or tab >>Pharmacodynamic Modelling of Irreversible and Reversible Gastric Proton Pump Inhibitors
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Acid related diseases like GERD, duodenal-and gastric ulcers and H. Pylori-positive peptic ulcer disease are primarily managed by reducing gastric acidity. Irreversible proton pump inhibitors (PPIs) inhibit gastric acid secretion effectively throughout the day by irreversibly inhibiting the gastric proton pump, H+, K+-ATPase, in the parietal cells. Reversible gastric proton pump inhibitors are under development, but have not yet reached clinical use.

The pharmacokinetic/pharmacodynamic (PK/PD) relationships of these compounds are nonlinear, with a delay in the effect-time profile compared to the plasma concentration-time course. PK/PD-modelling was used to characterize and quantify the pharmacological effect with regard to onset, intensity and duration of effect. Models based on functional data, that discriminate between drug-and system-specific parameters, were developed.

In general, the plasma concentration-time course for each individual was approximated by linear interpolation between time-points and served as input into the pharmacodynamic models. A turnover model of irreversible inhibition of gastric acid secretion by omeprazole in the dog described the data well. The model was challenged and found to be robust under different experimental conditions. This model could predict the effect following different exposure of omeprazole and following different histamine provocation. Different fitting approaches (naïve pooling, standard two-stage and nonlinear mixed effects modelling) were compared and resulted in similar parameter estimates. For the reversible inhibitors, a kinetic binding model was finally selected. With a binding model the delay in the effect-time profile is explained by prolonged binding to the enzyme.

Use of these results in drug development can be helpful with regard to selection of drugs for further development and to predict the first clinical dose.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 47 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 303
Keyword
Pharmacokinetics/Pharmacotherapy, Farmakokinetik/Farmakoterapi
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-3778 (URN)91-554-5806-8 (ISBN)
Public defence
2003-12-12, B22, Uppsala Biomedical Centre, Uppsala, 09:15
Opponent
Supervisors
Available from: 2003-11-20 Created: 2003-11-20Bibliographically approved

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PubMedhttp://jpet.aspetjournals.org/content/295/2/662.long

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Karlsson, Mats O.

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