Gastric acid secretion in the dog : a mechanism-based pharmacodynamic model for histamine stimulation and irreversible inhibition by omeprazole

• 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.

Nyckelord

PK/PD modeling

Omeprazole

H

K+-ATPase inhibitor

NONMEM

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