uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Gastric acid secretion in the dog: a mechanism-based pharmacodynamic model for histamine stimulation and irreversible inhibition by omeprazole
Show others and affiliations
2002 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 29, no 4, 365-382 p.Article in journal (Refereed) Published
Abstract [en]

A mechanism-based pharmacodynamic model was used to describe the inhibitory effect by omeprazole on gastric acid secretion measured after histamine stimulation in the dog. The model identifies parameters that are related to the physiological system, the histamine stimulation, and the irreversible effect of omeprazole on the H+, K(+)-ATPase enzyme. Four different experiments with omeprazole (Exps. 1-4) and two placebo experiments were performed in each of the four Heidenhain pouch dogs used. For placebo and experiments 1-3, saline or omeprazole 0.81 mumol/kg was infused during 3 hr with measurements of histamine-stimulated gastric acid secretion in two periods of 3.5-6.5 hr, one period starting just before the omeprazole infusion and a second later period up to 29 hr post infusion. In experiment 4, 0.18 mumol/kg of omeprazole was infused for 22.5 min and gastric juice was collected for 5 hr post infusion. The response data was well described by the model. Similar parameter estimates were obtained by three different analysis methods; naïve pooling, two-stage method and nonlinear mixed effects modeling. The elimination rate constant for the H+, K(+)-ATPase enzyme, kout, was estimated to be 0.040 hr-1, corresponding to a half-life of about 17 hr. This rate constant determines the duration of omeprazole inhibition after long-term exposure. For short-term omeprazole exposure the duration is determined by the rate constant for transfer of enzymes from active to resting state, estimated to be 1.88 hr-1. The second-order rate constant for histamine stimulation was estimated to be 0.064 hr-1 per histamine concentration unit and the maximum acid secretion was estimated to be 5.0 mmol H+/30 min. The second-order rate constant for the irreversible binding of omeprazole to H+, K(+)-ATPase, kome, was estimated to be 2.39 L/mumol.hr. By modeling the histamine-induced baseline response simultaneously with active treatment, predictions of the response are possible not only following different dosing regimens of omeprazole, but also following different degrees of histamine stimulation.

Place, publisher, year, edition, pages
2002. Vol. 29, no 4, 365-382 p.
Keyword [en]
PK/PD modeling, Omeprazole, H+, K+-ATPase inhibitor, NONMEM
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-91080DOI: 10.1023/A:1020905224001PubMedID: 12518709OAI: oai:DiVA.org:uu-91080DiVA: diva2:163670
Available from: 2003-11-20 Created: 2003-11-20 Last updated: 2011-10-07Bibliographically 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.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 303
Pharmacokinetics/Pharmacotherapy, Farmakokinetik/Farmakoterapi
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-3778 (URN)91-554-5806-8 (ISBN)
Public defence
2003-12-12, B22, Uppsala Biomedical Centre, Uppsala, 09:15
Available from: 2003-11-20 Created: 2003-11-20Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Karlsson, Mats O.
By organisation
Department of Pharmaceutical Biosciences
In the same journal
Journal of Pharmacokinetics and Pharmacodynamics
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 214 hits
ReferencesLink to record
Permanent link

Direct link