Omeprazole In Rats Research Articles

Effect of cimetidine and phenobarbital on metabolite kinetics of omeprazole in rats

Omeprazole (OMP) is a proton pump inhibitor used as an oral treatment for acid-related gastrointestinal disorders. In the liver, it is primarily metabolized by cytochrome P-450 (CYP450) isoenzymes such as CYP2C19 and CYP3A4. 5-Hyroxyomeprazole (5-OHOMP) and omeprazole sulfone (OMP-SFN) are the two major metabolites of OMP in human. Cimetidine (CMT) inhibits the breakdown of drugs metabolized by CYP450 and reduces the clearance of coadministered drug resulted from both the CMT binding to CYP450 and the decreased hepatic blood flow due to CMT. Phenobarbital (PB) induces drug metabolism in laboratory animals and human. PB induction mainly involves mammalian CYP forms in gene families 2B and 3A. PB has been widely used as a prototype inducer for biochemical investigations of drug metabolism and the enzymes catalyzing this metabolism, as well as for genetic, pharmacological, and toxicological investigations. In order to investigate the influence of CMT and PB on the metabolite kinetics of OMP, we intravenously administered OMP (30 mg/kg) to rats intraperitoneally pretreated with normal saline (5 mL/kg), CMT (100 mg/kg) or PB (75 mg/kg) once a day for four days, and compared the pharmacokinetic parameters of OMP. The systemic clearance (CLt) of OMP was significantly (p<0.05) decreased in CMT-pretreated rats and significantly (p<0.05) increased in PB-pretreated rats. These results indicate that CMT inhibits the OMP metabolism due to both decreased hepatic blood flow and inhibited enzyme activity of CYP2C19 and 3A4 and that PB increases the OMP metabolism due to stimulation of the liver blood flow and/or bile flow, due not to induction of the enzyme activity of CYP3A4.

The effect of immobilization stress on the pharmacokinetics of omeprazole in rats.

The effects of immobilization stress on the pharmacokinetics of omeprazole were studied in rats. The immobilization stress for 30 or 60 min immediately after oral administration of the drug caused an increase in the time to reach the maximum concentration. However, such stress did not alter the area under the plasma concentration-time curve (AUC). When administered intravenously, the half-life during the elimination phase was significantly prolonged by 30 min of immobilization stress, but the AUC value remained unchanged. The intestinal propulsive activity was significantly decreased by immobilization stress. These findings suggest that immobilization stress reduces gastrointestinal motility. A resulting delay during the absorption phase of omeprazole occurs, although the degree of influence on overall pharmacokinetics is relatively insignificant.

Anticonvulsant activity of omeprazole in rats

Omeprazole has long been used as an effective agent to treat peptic ulcer. Recent studies have shown that in addition to inhibiting the H +–K +ATPase, it also inhibits carbonic anhydrase (CA) types I, II and IV. This led us to investigate its anticonvulsant effect in a rat model of electroconvulsion. Since other carbonic anhydrase inhibitors like acetazolamide induce tolerance upon repeated use, we tested the tolerance potential of omeprazole upon repeated administration of up to 1 week. The animals were divided into four groups receiving normal saline, omeprazole 0.5, 1 or 2 mg/kg intraperitoneally. CC 50, i.e. the threshold current inducing tonic hind limb extension in 50% of the rats was established using a technoconvulsometer which delivers currents of varying intensity via ear clip electrodes. The CC 50 was established 30 min after injection of omeprazole. In another group of rats, omeprazole 2 mg/kg was given for 6 days and the CC 50 determined on days 0, 1, 3 and 6. Also the concentration of omeprazole in the brain was determined using high performance liquid chromatography. The CC 50 in vehicle-treated rats was 98 mA, which increased to 126, 135 and 162 mA with 0.5, 1 and 2 mg/kg of omeprazole, respectively. On repeat-dose studies the CC 50 on day 0 was 96 mA, on day 1 166 mA, on day 3 129 mA and on day 6 102 mA. The average brain concentration of omeprazole was 53.2±6.9 ng/g of brain tissue. In conclusion, this study has shown omeprazole to be an effective anticonvulsant, but rapidly develops tolerance to its anticonvulsant action. This study can stimulate interest in the development of agents with dual function — inhibition of CA as well as the accompanying Na +–K + ATPase — and such agents may prove to be effective anticonvulsants without exhibiting tolerance.

Identification of Metabolites of Omeprazole in Rats.

Identification of Metabolites of Omeprazole in Rats.

Antisecretory and antiulcer effects of YM020, a new H+,K(+)-ATPase inhibitor, in rats and dogs.

We examined the effects of YM020 (3-cyanomethyl-2-methyl-8-[(3-methyl-2-butenyl)oxy]-imidazo[1,2- a]pyridine), a novel H+,K(+)-ATPase inhibitor, on gastric acid secretion and experimental gastroduodenal lesions in rats and dogs. Intraduodenal, subcutaneous and oral YM020 inhibited basal gastric acid secretion in pylorus-ligated rats with ED50 values of 9.1, 9.1 and 9.5 mg/kg, respectively. Oral pretreatment with YM020 5 hr before ligation still suppressed acid secretion, with a potency a little less than that of omeprazole. In anesthetized dogs, intravenous YM020 inhibited histamine-, methacholine- and pentagastrin-induced gastric acid secretion with ED50 values of 0.05, 0.01 and 0.08 mg/kg, respectively. In Heidenhain pouch dogs, although oral YM020 (3 mg/kg) inhibited histamine-induced acid secretion, acid output returned to control levels faster than in dogs treated with omeprazole. Oral YM020 inhibited the formation of water-immersion restraint stress-, indomethacin-, absolute ethanol-, 0.7 N hydrochloric acid- and cysteamine-induced gastric or duodenal lesions with ED50 values of 2.9, 4.3, 2.0, 11.7 and 8.4 mg/kg, respectively. Moreover, subcutaneous YM020 also suppressed the formation of ethanol- and HCl-induced gastric lesions. These results suggest that YM020 has an antisecretory effect almost the same as or 2 to 3 times weaker than those of omeprazole and that its duration is not as long as that of omeprazole in rats and dogs. Furthermore, YM020 possesses a cytoprotective effect and the mechanism of YM020 may be different to that of omeprazole.

First-Pass Metabolism of Omeprazole in Rats

To clarify thein vivofirst-pass metabolism of omeprazole, the pharmacokinetics were examined after oral, intraduodenal (id), intraportal venous (ipv), and intravenous (iv) administration at various doses to rats. Extraction ratios in the liver and intestinal tract were determined from the areas under the concentration-time curve (AUC) for ipv and iv administration and from those for id and ipv administration, respectively. Assuming that the drug was absorbed from the gastrointestinal tract completely, the hepatic and intestinal extraction ratios were 0.80, 0.63, and 0.59 at doses of 2.5, 5, and 10 mg/kg and 0.70 and 0.73 at doses of 5 and 10 mg/kg, respectively. The bioavailability of orally administered omeprazole was 6.4, 9.6, and 12.6% at the doses of 10, 20, and 40 mg/kg, respectively. There were no differences in the distribution volume of steady state, total clearance, or elimination half-life at any doses. In addition, the AUC value after oral administration (20 mg/kg) in rats acutely intoxicated with CCI4was 2.4 times larger than that in the control. These findings suggest that omeprazole undergoes a first-pass metabolism in the intestinal mucosa and/or lumen, as well as in the liver, and that the major contribution to the dose-dependent increase in bioavailability is a saturation of the first-pass metabolism in the liver.

P-546 - First-pass effect of omeprazole in rats.

P-546 - First-pass effect of omeprazole in rats.

Role of histamine2 receptor in increased expression of rat gastric H(+)-K(+)-ATPase alpha-subunit induced by omeprazole.

Omeprazole is a specific inhibitor in vivo of the functioning gastric acid pump, the H(+)-K(+)-adenosinetriphosphatase (ATPase), in the secretory canaliculus of the parietal cell. It has been shown previously that omeprazole in rats led to an increase in the mRNA for the alpha-subunit of the H(+)-K(+)-ATPase. Omeprazole causes a marked increase in circulating gastrin in this species, which in turn stimulates release of histamine from the enterochromaffin-like cell. The possible role of this pathway was investigated by the in vivo administration of famotidine, a potent H2 receptor antagonist. A single intraperitoneal dose of famotidine, 200 mg/kg, produced a transient hypergastrinemia peaking at 3 h and normalizing at 12 h, inhibition of secretion that lasted for 12 h, but no change in the level of the alpha-subunit mRNA or of beta-actin mRNA. In contrast, a single dose of omeprazole, 100 mg/kg, inhibited acid secretion and produced hypergastrinemia, peaking at 12 h, both effects lasting for the 24-h observation period. Omeprazole elevated the alpha-subunit mRNA transiently by more than threefold at 3 h, with normal levels being restored at 24 h. The administration of famotidine 1 h after omeprazole did not change the effects of omeprazole on acid secretion but elevated the gastrin levels further. There was now no elevation of the alpha-subunit mRNA for the first 6 h, but a small increase at 12 h and a further increase to approximately 2.5-fold at 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in gastric mucosal morphology induced by long-term treatment with omeprazole in rats.

The effects of long-term treatment with omeprazole on the gastric mucosal morphology was studied. Eighty male Sprague-Dawley rats were used and divided into 4 equal groups. Half of the animals in 3 of the groups were given omeprazole, 40 mumol/kg body weight, orally once daily for 130 days. The remaining rats in these groups served as controls. Half of the rats in the fourth group were given subcutaneous injections with pentagastrin, this group received vehicle only. At the end of the treatment period, all animals were killed by vascular perfusion with fixative and the gastric corpus mucosae prepared for light and electron microscopy. Quantitative morphometry was used to evaluate eventual effects of treatment on the different epithelial cell types which are present in the corpus mucosa. Omeprazole treatment resulted in an increased mucosal thickness as a result of a proportional increase in all types of epithelial cells with the exception of the endocrine cells. These cells increased in number by 100%. A similar increase was seen after pentagastrin treatment. In the omeprazole-treated rats, there was also an increase in the size and number of pepsinogen granules within the zymogen cells. All changes in gastric mucosal morphology seen after 130 days of treatment with omeprazole turned out to be reversible and were not seen after a recovery period of 3 months.