omeprazole, Prilosec
The hydroxylation of omeprazole correlates with S-mephenytoin and proguanil metabolism.

Kortunay S, Basci NE, Bozkurt A, Isimer A, Sayal A, Kayaalp SO.

Hacettepe University, Faculty of Medicine, Department of Pharmacology, Ankara, Turkey.

OBJECTIVES: This pharmacogenetic study was aimed at studying the pattern of oxidation of omeprazole in a Turkish population and testing whether omeprazole metabolism cosegregates with the genetically determined metabolism of mephenytoin and proguanil in Turkish subjects. METHODS: The hydroxylation of omeprazole was measured in 116 unrelated healthy Turkish subjects after administration of a single oral dose of omeprazole (20 mg), using the ratio of omeprazole to 5-hydroxyomeprazole in plasma 3 h after dosing. To 31 subjects, who were phenotyped with omeprazole, mephenytoin (100 mg, p.o.) or proguanil (200 mg, p.o.) were administered at least 1 week apart. The S/R ratio of mephenytoin and the ratio of proguanil to cycloguanil were determined from an 8-h urine collection. RESULTS: Based on the distribution of the log (omeprazole/hydroxyomeprazole) values and using the antimode value of 0.8, the frequency of poor metabolizers of omeprazole was estimated to be 7.7% (95% confidence interval 3-18%) which was similar to that in the other Caucasian populations (P = 0.54, Fisher's exact test). Three poor metabolizers of omeprazole were also classified as poor metabolizers of both mephenytoin and proguanil and no misclassification occurred with three phenotyping methods. All three methods separated poor or extensive metabolizer phenotypes with complete concordance. The ratio of omeprazole to hydroxyomeprazole correlated with the S/R ratio of mephenytoin and the ratio of proguanil to cycloguanil. CONCLUSION: These results support the hypothesis that the oxidative metabolism of three different drugs may be catalyzed by the same cytochrome P450 enzyme.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9476042&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Differences in pH-dependent activation rates of substituted benzimidazoles and biological in vitro correlates.

Kromer W, Kruger U, Huber R, Hartmann M, Steinijans VW.

Department of Pharmacology, Byk Gulden, Konstanz, Germany.

Gastric proton pump inhibitors (PPIs) are substituted benzimidazole prodrugs that require an acid-induced activation. Its rate depends on the reactivity of the molecule relative to the environmental pH and determines the drug's tissue selectivity. Factors affecting the exposure of moderately acidic tissues to the activated PPI are the area under the serum concentration-time curve (AUC), serum protein binding, the partition coefficient logP and the serum elimination half-life relative to the chemical activation half-life at a critical tissue pH of about 5. These parameters have therefore been determined in a comparative fashion in the present study. The data shows that pantoprazole is less likely to undergo unwanted activation at moderately acidic targets as opposed to the parietal cell, compared to omeprazole. Actually, although 40 mg pantoprazole (steady state) gave a slightly higher serum AUC of the total parent compound than 40 mg omeprazole (10.5 vs. 7.1 micromol x h x l[-1]), a higher serum protein binding of pantoprazole versus omeprazole (98 vs. 96%) reversed the AUC values for the free drug in favor of a lower value for pantoprazole (0.19 vs. 0.28 micromol x h x l[-1]). It is the free parent compound that equilibrates across cell membranes to be activated in acidic tissue compartments. At pH 5.1, the activation half-life of pantoprazole was 4.7 versus 1.4 h for omeprazole, the latter being in the order of the common serum elimination half-life determined in an intraindividual comparison (1.24 vs. 1.25 h). Thus, pantoprazole is eliminated faster from blood than it is activated at a pH of about 5, while omeprazole is as quickly activated at this pH as it is eliminated from blood. Biological in vitro experiments confirmed that pantoprazole displays a lower liability to interfere with unwanted biological targets. This has been demonstrated in vitro for inhibition of both renal Na+/K+-ATPase, lysosomal acidification and the production of reactive oxygen species by neutrophils.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9494064&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Lack of pharmacokinetic interaction between mexiletine and omeprazole.

Kusumoto M, Ueno K, Tanaka K, Takeda K, Mashimo K, Kameda T, Fujimura Y, Shibakawa M.

Department of Pharmacy, Maizuru Kyosai Hospital, Kyoto, Japan.

OBJECTIVE: To investigate the effect of omeprazole on the pharmacokinetics of mexiletine. METHODS: Nine healthy male Japanese volunteers participated in a crossover study. On day 1, the subjects received mexiletine 200 mg. On days 2-7, they received omeprazole 40 mg, and on day 8 they received mexiletine 200 mg and omeprazole 40 mg concomitantly. Serum concentrations of mexiletine were determined just before drug administration and at 1, 2, 3, 4, 6, 8, 12, and 24 hours on day 1 and day 8. RESULTS: No differences in mexiletine concentrations were observed between the two phases of the study. The mean AUCs after administration of mexiletine alone and in combination with omeprazole 40 mg/d were 6.26 and 6.20 ng.h/L, respectively. CONCLUSIONS: These findings suggest that omeprazole does not affect mexiletine metabolism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9496401&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Cure of Helicobacter pylori infection by omeprazole-clarithromycin-based therapy in non-human primates.

Dubois A, Berg DE, Fiala N, Heman-Ackah LM, Perez-Perez GI, Blaser MJ.

Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA.

Rhesus monkeys raised in colonies tend to become naturally infected by Helicobacter pylori early in life. Earlier attempts to cure H. pylori infection with a 10-day triple therapy (metronidazole, amoxicillin, and peptobismol) were only partially (60%) successful, probably because of preexisting metronidazole resistance. This study was carried out to determine the efficacy of an alternative clarithromycin-omeprazole-based therapy for curing H. pylori infection in Rhesus monkeys (Macaca mulatta), and to examine histologic and serologic correlates of curing. Five monkeys were endoscoped under ketamine anesthesia. Histology and culture of gastric biopsies and serologic tests demonstrated that they were H. pylori-positive. Two animals had not received prior anti-H. pylori treatment, while three other animals had failed triple therapy and carried metronidazole-resistant H. pylori strains. Quadruple therapy with omeprazole, clarithromycin, amoxicillin, and bismuth subsalicylate was given for 10 days to these five animals. All five animals were cured of the infection, and remained H. pylori-free, based on histology and culture at regular intervals for the 5 months posttherapy during which they were followed. Gastritis scores and anti-H. pylori IgG levels decreased in each animal during this period to levels characteristic of uninfected animals. These results indicate that an omeprazole-clarithromycin-based regimen can cure H. pylori infection in Rhesus monkeys, with resolution of abnormal histology and serologic responses. They suggest that this preclinical animal model is useful for testing new anti-H. pylori therapies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9497216&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Omeprazole in infants with cimetidine-resistant peptic esophagitis.

Alliet P, Raes M, Bruneel E, Gillis P.

Department of Pediatrics, Virga Jesse Hospital, Hasselt, Belgium.

Twelve neurologically normal infants (age 2.9+/-0.9 months) with peptic esophagitis (grade 2) who did not respond to cimetidine (in addition to positioning, cisapride, and Gaviscon) were treated with omeprazole, 0.5 mg/kg once a day, for 6 weeks. The effectiveness of omeprazole was evaluated in all infants by clinical assessment and endoscopy before and after treatment and by 24-hour gastric pH monitoring during treatment in seven infants. Omeprazole therapy led to a marked decrease in symptoms, endoscopic and histologic signs of esophagitis, and intragastric acidity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9506656&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Omeprazole induces altered bile acid metabolism.

Shindo K, Machida M, Fukumura M, Koide K, Yamazaki R.

First Department of Internal Medicine, Yokohama City University, School of Medicine, Japan.

BACKGROUND: It has been reported that the acidity of gastric contents could be an important factor in regulating jejunal flora. AIMS: To investigate the effects of omeprazole induced changes in gastric pH on jejunal flora and bile acid metabolism. METHODS: Twenty one patients with gastric ulcer and 19 healthy volunteers were studied. Deconjugation of bile acids was detected using a bile acid breath test. Jejunal fluid was aspirated using a double lumen tube with a rubber cover on the tip and deconjugation was examined using thin layer chromatography. Fat malabsorption was detected by a triolein breath test. RESULTS: In the bile acid breath test, expired breath samples from all patients and healthy volunteers showed significantly greater 14CO2 specific activity after omeprazole treatment (20 mg/day) than before treatment. Bacterial overgrowth was found in the jejunal fluid and gastric juice of both ulcer patients and healthy volunteers after omeprazole treatment. The following species were identified: Escherichia coli, Candida albicans, enterococcus, Lactobacillus bifidus, Bacteroides vulgatus, B uniformis, Eubacterium lentum, Eu parvum, and Corynebacterium granulosum. All of these species, except E coli and C albicans, deconjugate bile acids. There was a significant correlation between 14CO2 activity and gastric pH, both before and after omeprazole treatment in both groups. The triolein breath test revealed impaired fat absorption in both groups after omeprazole treatment. CONCLUSIONS: Both patients with gastric ulcer and healthy volunteers exhibited increased deconjugation of bile acids caused by bacterial overgrowth in the jejunum and fat malabsorption after omeprazole treatment. The bacterial over-growth consisted of both anaerobes and aerobes with deconjugation ability and was probably associated with an omeprazole induced shift to neutral pH in the gastric juice.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9536953&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
A cost-utility analysis comparing omeprazole with ranitidine in the maintenance therapy of peptic esophageal stricture.

Stal JM, Gregor JC, Preiksaitis HG, Reynolds RP.

Department of Medicine, University of Western Ontario, London.

BACKGROUND: Recent studies have suggested that patients receiving omeprazole for prophylaxis against peptic esophageal stricture recurrence have less dysphagia and require fewer repeat dilations than patients receiving ranitidine. OBJECTIVE: To estimate the incremental utility gain and associated incremental cost of omeprazole compared with those of ranitidine for the maintenance therapy of patients with peptic stricture who required esophageal dilation. METHODS: Decision analysis using SMLTREE software was used to compare the incremental cost-utility of omeprazole 20 mg once daily with that of ranitidine 150 mg bid for one year. Variables were estimated from the literature, hospital data, and utility analyses involving patients with peptic stricture and health professionals. The primary outcome measure was cost per quality-adjusted life-years (QALYs) gained. RESULTS: The incremental cost of omeprazole compared with that of ranitidine was $556 per patient treated. The incremental utility gain of omeprazole was 0.0112 QALYs. Overall, the incremental cost:utility ratio of omeprazole in the maintenance therapy of patients with peptic stricture was $49,600 per QALY gained. A sensitivity analysis revealed that the estimates with the greatest impact on the cost:utility ratio were disutility associated with dysphagia and dilation, the probability of requiring redilation and the cost of medications. CONCLUSIONS: Omeprazole 20 mg once daily is associated with greater utility and higher cost than ranitidine 150 mg bid when used as prophylaxis against stricture recurrence. Omeprazole may be considered clinically and economically sufficient enough to warrant widespread use in this setting.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9544411&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Growth inhibitory and bactericidal activities of lansoprazole compared with those of omeprazole and pantoprazole against Helicobacter pylori.

Nakao M, Malfertheiner P.

Pharmaceutical Research Laboratories III, Takeda Chemical Industries Ltd., Osaka, Japan.

BACKGROUND: Helicobacter pylori plays a role in the pathogenesis of both duodenal and gastric ulcers. The aim of this study was to evaluate the effect of the proton pump inhibitor (PPI), lansoprazole, commonly used in eradication regimens, on growth, bactericidal activity and morphology of H. pylori in vitro in comparison with other PPIs. MATERIALS AND METHODS: Growth inhibitory activity of each of the PPIs was evaluated by determining minimum inhibitory concentrations using an agar dilution method. Bactericidal activity was determined by analysis of the viable cells in culture at various time points after incubation with different concentrations of the PPIs. Bacterial morphology was examined using scanning electron microscopy of fixed cells after exposure to the test substances. Urease activity in cell extracts of H. pylori that had been incubated with increasing concentrations of the PPIs was determined by colorimetry. RESULTS: The growth inhibitory activity of lansoprazole was significantly more potent than that of omeprazole or pantoprazole (MIC90 6.25 vs. 25 and 100 micrograms/ml, respectively). Exposure of H. pylori to lansoprazole produced loss of viability and an aberrant bacterial morphology, which was more extensive than seen with omeprazole or pantoprazole. Lansoprazole dose dependently inhibited urease activity; its effectiveness was comparable with omeprazole but more potent than pantoprazole. CONCLUSIONS: The mechanism of action that leads to loss of viability of H. pylori cells appears to differ between the three PPIs investigated; lansoprazole was the most potent of the three agents in terms of growth inhibition and disruption of bacterial morphology.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9546114&dopt=Abstract omeprozole Prilosec