EFFECT OF 7 YEARS DAILY ORAL-ADMINISTRATION OF OMEPRAZOLE TO BEAGLE DOGS

Ten beagle dogs were given omeprazole orally at a dose of 0.17 mg/kg ( 0.5 mu mol/kg) daily for 7 years. Six dogs served as controls. Regular ly evaluated criteria were clinical signs, body weight, food consumpti on, rectal temperature, electrocardiography, hematology, blood chemist ry, urinalysis, ophthalmoscopy, gastroscopic examination including gas tric mucosal biopsy sampling for histological evaluation, pharmacokine tics of omeprazole, and plasma gastrin levels. After approximately 5 y ears, a quantitative gastric acid secretion test was performed. No tre atment-related adverse clinical signs or effects were observed in the dogs, and all animals survived to term. The annual gastroscopy with hi stological examinations of gastric mucosa did not show any treatment-r elated changes. At all investigations and in all dogs, the parietal ce lls were morphologically normal, and there were no changes of pattern or any increase in the number of argyrophil enterochromaffin-like cell s compared to the control animals. In the plasma samples collected 24 h after dosing, there were no significant differences in either basal or meal-stimulated gastrin levels between the controls and the omepraz ole-treated animals. Peak plasma concentration of omeprazole occurred within 2 h of dosing. The area under the concentration curve (AUC) was not affected by dosing over 7 years and was in good agreement with th e AUC in humans given a dose of 20 mg omeprazole daily. Acid secretion tests after 5 years of treatment showed that the mean inhibition of a cid secretion by omeprazole 4-7 h after dosing was as expected - about 50%. It is concluded that 7 years' treatment with omeprazole in dogs, in a dose resulting in clinically relevant plasma concentrations, did not cause any adverse effects in any of the animals. Furthermore, the degree of acid inhibition of a submaximal dose of omeprazole is maint ained during long-term treatment without any signs of tachyphylaxis.