omeprazole, Prilosec
Effects of antisecretory agents on parietal cell structure and H/K-ATPase levels in rabbit gastric mucosa in vivo.

Scott DR, Besancon M, Sachs G, Helander H.

Laboratory of Membrane Biology, Veterans Administration Medical Center West Los Angeles, Wadsworth Division, California 90073.

The effect of inhibition of acid secretion on parietal cell morphology and the concentration of H,K-ATPase alpha-subunit protein was determined by electron microscopy and western blotting. Omeprazole or famotidine alone or in combination were used. Control animals showed a morphological stimulation index (0 = resting, 1.0 = fully stimulated) of 0.60; omeprazole treatment (1 mg/kg, twice a day) resulted a stimulation index of 0.63, famotidine injection (20 mg/kg twice a day) an index of 0.11, famotidine infusion (0.2 mg/hr) for five days an index of 0.38, and the combination of omeprazole and famotidine injection twice a day gave an index of 0.02. No change in the frequency of degenerating or damaged parietal cells was observed in any of the groups. In control animals, the number of lysosomes was 0.9/cell, with famotidine 1.8 and with omeprazole 5.6/cell. H/K-ATPase levels fell by about 25% with omeprazole and rose by about 23% with famotidine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7924730&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
A pharmacokinetic study comparing single and repeated oral doses of 20 mg and 40 mg omeprazole and its two optical isomers, S-omeprazole (esomeprazole) and R-omeprazole, in healthy subjects.

Hassan-Alin M, Andersson T, Niazi M, Rohss K.

Experimental Medicine, AstraZeneca R & D Molndal, 43183, Molndal, Sweden. mohammed.hassan-alin astrazeneca.com

OBJECTIVE: To investigate the pharmacokinetics of S-omeprazole (esomeprazole), R-omeprazole and racemic omeprazole following single and repeated oral doses of 20 mg and 40 mg of each compound in healthy male and female subjects. METHODS: In an open, randomised, three-way, cross-over study, 12 subjects received 20 mg and another 12 subjects received 40 mg S-omeprazole, R-omeprazole and racemic omeprazole as oral solutions once daily for 5 days, separated by washout periods of at least 10 days. Blood samples were taken for analysis pre-dose and at selected time points during a 12-h period following drug administration on study day 1 and day 5. Pharmacokinetic parameters of S-omeprazole, R-omeprazole, racemic omeprazole and the two main metabolites (5-hydroxy and sulphone) were calculated using non-compartmental analysis. RESULTS: Following the 20-mg dose of each compound, values of the total area under the plasma concentration-time curve (AUC) were 1.52, 0.62 and 1.04 micromol h/l for S-omeprazole, R-omeprazole and racemic omeprazole, respectively, on day 1. Respectively, AUC values on day 5 were 2.84, 0.68 and 1.63 micromol h/l. Corresponding values after the 40-mg doses were 3.88, 1.39 and 2.44 micromol h/l on day 1 and 9.32, 1.80 and 5.79 micromol h/l on day 5. CONCLUSION: Treatment with S-omeprazole (esomeprazole; 20 mg and 40 mg) resulted in higher AUC values than with either R-omeprazole or racemic omeprazole after both single and repeated doses due to a lower metabolic rate of S-omeprazole than R-omeprazole and, consequently, racemic omeprazole. S-Omeprazole, R-omeprazole and the racemate were well tolerated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15578172&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Specific and dose-dependent enzyme induction by omeprazole in human beings.

Rost KL, Brosicke H, Heinemeyer G, Roots I.

Institute of Clinical Pharmacology, Klinikum Steglitz, Free University of Berlin, Germany.

Omeprazole induces hepatic cytochrome P-4501A2. In a previous study this effect was shown to be significant in vivo in 6 poor metabolizers, including 1 intermediate metabolizer, but not in 12 extensive metabolizers of S-mephenytoin after 7 days of treatment with 40 mg/day omeprazole. In this study, the specificity of the inducing potential of omeprazole was investigated in these volunteers. Furthermore, in eight of the extensive metabolizers the dose-dependence of cytochrome P-450 1A2 induction was evaluated. Cytochrome P-450 1A2 activity was monitored by means of the 13C-[N3-methyl]caffeine breath test and by means of plasma caffeine clearance before omeprazole treatment with 120 mg/day, on the seventh day of dosage and after a 7-day washout. Omeprazole plasma concentration was measured. Results were compared with those after 40 mg. gamma-Glutamyltransferase activity in serum, as well as urinary excretion of D-glucaric acid and 6 beta-hydroxycortisol, were measured on the same study days in all study groups (n = 26). In the eight extensive metabolizers the breath test indicated a dose-dependent increase of cytochrome P-450 1A2 activity of 8.5% +/- 15.0% (40 mg, mean +/- SD, NS) and 27.2% +/- 16.5% (120 mg, p = 0.002). Caffeine clearance was increased by 31.6% +/- 20.7% (p < 0.001) with the higher dose. None of the study groups exhibited a significant increase of gamma-glutamyltransferase activity or urinary excretion of D-glucaric acid or 6 beta-hydroxycortisol. This was in contrast to the phenobarbital-type induction observed after treatment with antiepileptic drugs. Induction by omeprazole seems to be restricted to cytochrome P-450 1A enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7927253&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
YM022 [(R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl- 1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea], a potent and selective gastrin/cholecystokinin-B receptor antagonist, prevents gastric and duodenal lesions in rats.

Nishida A, Takinami Y, Yuki H, Kobayashi A, Akuzawa S, Kamato T, Ito H, Yamano M, Nagakura Y, Miyata K.

Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Japan.

We evaluated the effect of YM022 [(R)-1-[2,3-dihydro-1-(2'- methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3- (3-methylphenyl)urea], a potent and selective gastrin/cholecystokinin-B receptor antagonist, on gastric acid secretion and gastric and duodenal lesions in rats. Oral YM022 (0.1-10 mumol/kg), famotidine (0.3-30 mumol/kg) and omeprazole (3-100 mumol/kg) dose-dependently suppressed acid secretion in pylorusligated rats with ED50 values of 0.83, 1.63 and 10.9 mumol/kg, respectively. YM022 (1-10 mumol/kg p.o.), famotidine (1-10 mumol/kg p.o.) and omeprazole (10-100 mumol/kg p.o.) prevented indomethacin-induced gastric lesions in a dose-related manner. The potency of YM022 was comparable to that of famotidine and was 8 times greater than that of omeprazole. YM022 and famotidine partially inhibited gastric damage induced by water-immersion and restraint stress, whereas omeprazole abolished these lesions. In an acidified ethanol-induced gastric injury model, all three drugs inhibited the formation of erosions. The YM022 dosage required in this model was much greater than that required in the inhibition of gastric acid. The inhibitory effect of YM022 was partially reversed by indomethacin, indicating the involvement of a prostaglandin-mediated pathway. YM022 (3-100 mumol/kg p.o.), famotidine (1-30 mumol/kg p.o.) and omeprazole (3-100 mumol/kg p.o.) inhibited mepirizole-induced duodenal ulcers. On the basis of ED50 values, YM022 was 5 times less potent than famotidine and as potent as omeprazole against mepirizole-induced duodenal ulcers. These results suggest that YM022 possesses antisecretory and antiulcer activities that are as potent as those of famotidine in rats and that YM022 represents a useful therapeutic agent in the treatment of peptic ulcer disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7932178&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Liver regeneration is enhanced by omeprazole in rats following partial hepatectomy.

Ohtake M, Aono T, Sakaguchi T, Tsukada K, Hatakeyama K.

Department of Surgery, Niigata University School of Medicine, Japan.

The effect of omeprazole on liver regeneration was studied in rats following partial (65 per cent) hepatectomy. Omeprazole 0.2 mg/kg increased the relative liver weight (weight of liver as a proportion of body-weight) and mitotic index (P < 0.05). There was no difference in food and water intake. The serum gastrin concentration was significantly higher in animals receiving omeprazole 0.2 mg/kg than in controls (P < 0.05). Omeprazole administration induced an increase in the level of serum alkaline phosphatase (P < 0.05) but had no effect on serum albumin, glutamic-pyruvic transaminase and total bilirubin levels. Omeprazole stimulates liver regeneration after partial hepatectomy and this regeneration may be mediated by gastrin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7953355&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
First-pass metabolism of omeprazole in rats.

Watanabe K, Furuno K, Eto K, Oishi R, Gomita Y.

Department of Hospital Pharmacy, Okayama University Medical School, Japan.

To clarify the in vivo first-pass metabolism of omeprazole, the pharmacokinetics were examined after oral, intraduodenal (i.d.), intraportal venous (i.p.v), and intravenous (i.v.) 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 i.p.v. and i.v. 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 CCl4 was 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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7983597&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Effects of NC-1300-O-3 on gastric mucus secretion and prostaglandin release in rats.

Matsukura H, Masuda M, Uchida A, Kamishiro T.

Research Laboratories, Nippon Chemiphar Co., Ltd., Saitama, Japan.

We investigated the effect of NC-1300-O-3 on gastric mucus secretion and prostaglandin release into the gastric lumen in rats. NC-1300-O-3 following single or repeated administration for up to 4 weeks significantly increased the hexose content in the gastric lumen at 10 to 100 mg/kg, p.o. Omeprazole and cimetidine at doses that strongly inhibited gastric acid secretion had no effect on the hexose content following single or repeated administration for 8 days. When administered repeatedly for 8 days, NC-1300-O-3, omeprazole and cimetidine significantly decreased the hexosamine content in gastric surface mucosa, but significantly increased gastric mucus secretion was observed at the same time only with NC-1300-O-3, indicating that this agent has a profile of action on gastric mucus metabolism different from those of omeprazole and cimetidine. NC-1300-O-3 at 10 and 30 mg/kg, p.o. and omeprazole at 30 mg/kg, p.o. increased the release of prostaglandins into the gastric lumen, and this was markedly inhibited by pretreatment with indomethacin, suggesting that these agents may enhance prostaglandin biosynthesis in the gastric mucosa. From these results, it seems that the enhancement of NC-1300-O-3 on gastric mucus secretion and prostaglandin biosynthesis in the gastric mucosa contribute to the antiulcer effect of NC-1300-O-3.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7990269&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Gastrointestinal uptake of FDG after N-butylscopolamine or omeprazole treatment in the rat.

Yamamoto F, Nakada K, Zhao S, Satoh M, Asaka M, Tamaki N.

Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan. fumiyasu xb4.so-net.ne.jp

OBJECTIVE: Gastrointestinal (GI) uptake of 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) is frequently observed in whole-body positron emission tomography (PET) images. Such physiological uptake may interfere with accurate interpretation. The aim of the present study was to determine whether physiological gastrointestinal FDG uptake can be decreased by means of an antiperistaltic agent, N-butylscopolamine, or a gastric secretion inhibitor, omeprazole. METHODS: Sprague-Dawley rats were divided into three groups: omeprazole-treated (n = 6), N-butylscopolamine-treated (n = 7), and control group (n = 6). The rats in the omeprazole-treated group were administered omeprazole (1.0 mg/kg) intravenously 45 minutes before FDG injection. The rats in the N-butylscopolamine-treated group were administered N-butylscopolamine (1.0 mg/kg) intramuscularly 10 minutes before FDG injection. Sixty minutes after FDG injection under overnight fasting state, the gastrointestinal tissues were excised and weighed to determine the radioactivity of 18F using a gamma counter. RESULTS: The mean values of FDG uptake in the esophagus, stomach, small intestine, cecum and colon of the N-butylscopolamine-treated group vs. the omeprazole-treated group were 148% vs. 162%, 109% vs. 113%, 113% vs. 88%, 102% vs. 85%, 105% vs. 70% of the control group, respectively. There were no statistical differences in FDG uptake rate in the esophagus, stomach, or cecum among the three groups. FDG uptake rates in the small intestine and colon of the omeprazole-treated group were significantly lower than those in the control group. CONCLUSION: Physiological FDG uptake in the GI tract was not decreased by the administration of N-butylscopolamine. Omeprazole was effective in decreasing FDG uptake in the small intestine and colon. Omeprazole has a potential to decrease FDG uptake rate in a limited part of the GI tract.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15586641&dopt=Abstract omeprozole Prilosec