omeprazole, Prilosec
Omeprazole determination using HPLC with coulometric detection.

Sluggett GW, Stong JD, Adams JH, Zhao Z.

Analytical Research and Development, Merial Ltd., North Brunswick, NJ 08902, USA. gregory.sluggett merial.com

A sensitive high performance liquid chromatography (HPLC) method for the determination of omeprazole and three related benzimidazoles is reported. Coulometric detection was carried out at +800 mV using a porous carbon electrode. The linear range is 0.01-10 microg/ml. The method has a high degree of precision; the relative standard deviation of omeprazole at a concentration of 1.06 microg/ml was 0.7% (n=4). The cyclic voltammogram of omeprazole is consistent with the hydrodynamic voltammogram exhibiting a single major irreversible oxidative wave with a peak potential at +1105 mV. The response factors for the four compounds are similar indicating that the oxidative process does not involve the sulfur moiety exclusively. The data are most consistent with oxidation primarily of the benzimidazole groups. The method was applied successfully to the determination of omeprazole in a paste formulation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11377014&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Anticonvulsant activity of omeprazole in rats.

Balakrishnan S, Bhargava VK, Pandhi P.

Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.

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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11395292&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
An optimized methodology for combined phenotyping and genotyping on CYP2D6 and CYP2C19.

Tamminga WJ, Wemer J, Oosterhuis B, Brakenhoff JP, Gerrits MG, de Zeeuw RA, de Leij LF, Jonkman JH.

Pharma Bio-Research Group BV, Science Park, NL-9471 GP Zuidlaren, The Netherlands. WTamminga PBR.NL

A method for simultaneous phenotyping and genotyping for CYP2D6 and CYP2C19 was tested. Six healthy volunteers were selected (three extensive and three poor metabolisers for CYP2D6). CYP2D6 was probed with dextromethorphan and metoprolol and CYP2C19 was probed with omeprazole. Blood samples were collected and analysed for dextromethorphan, dextrorphan, metoprolol, alpha-hydroxymetoprol, omeprazole and 5-hydroxyomeprazole by HPLC. Genotyping was performed for both CYP2D6 and CYP2C19. Generally, plasma levels could be measured up to 8 h post-dose except for alpha-hydroxymetoprolol in poor metabolizers (PMs) and dextromethorphan in extensive metabolizers (EMs) (35% below quantification limit). The correlation between the metabolic ratio based on timed individual measurements and the metabolic ratio based on the AUC0-12 values was significant at 3 h post-dose for all probes. In conclusion, the following procedure is suggested: administer metoprolol (100 mg) and omeprazole (40 mg); after 3 h, take a blood sample to assess the genotype and the metabolic ratio for CYP2D6 (metoprolol over alpha-hydroxymetoprolol) and CYP2C19 (omeprazole over 5-hydroxyomeprazole) in plasma. With this procedure, all necessary information on the individual CYP2D6 and CYP2C19 metabolising capacity can be obtained in a practical, single-sample approach.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11417446&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Effect of long-term, continuous versus alternate-day omeprazole therapy on serum gastrin in patients treated for reflux esophagitis.

Ligumsky M, Lysy J, Siguencia G, Friedlander Y.

Gastroenterology Unit, Division of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.

BACKGROUND: Proton pump inhibitors have been proven to have a major role in the management of peptic diseases, especially the long-term control of reflux esophagitis. The potent inhibitory effect of omeprazole on gastric acid secretion is frequently associated with hypergastrinemia, and gastrin and its intermediates have been reported to promote gastrointestinal cellular functions and cell growth. Experimental data suggest that gastrin may affect the proliferation of colon cells and some other cancer cells. However, so far the direct role of gastrin in tumorigenesis is unclear. Although most clinical studies on long-term treatment with omeprazole or other proton pump inhibitors do not report serious adverse effects, the issue of prolonged hypergastrinemia and tissue growth is unsettled, and many clinicians are reluctant to recommend long-term use of omeprazole or of other proton pump inhibitors. STUDY: We examined the effect of long-term omeprazole treatment on serum gastrin levels in patients with reflux esophagitis when given either 20 mg daily (group 1) or on alternate days (group 2). During the follow-up period, clinical remission was monitored and maintained in all patients in group 1 and in the majority of patients in group 2. RESULTS: The mean serum gastrin level was significantly elevated in group 1 (mean +/- SE, 159 +/- 23.6 pg/mL; range, 45-620 pg/mL; n = 31) as compared with the alternate-day treatment group (group 2) (66 +/- 4.8 pg/mL; range, 37-115 pg/mL; n = 21) (p < 0.005). In controls, serum gastrin levels showed similar values to those found in group 2 (54 +/- 4.3 pg/mL; range, 27-94 pg/mL; n = 20). Fourteen patients (45%) in group 1 had serum gastric ranging from 140 to 620 pg/mL, and 8 (25%) had a 6-fold or greater increase in serum gastrin. The follow-up treatment period ranged between 3 and 60 months (mean +/- SE, 16.1 +/- 2.1 months) for group 1 and 3-36 months (9.7 +/- 1.4 months) for group 2. Upon multivariate adjustment for age and duration of treatment, a significantly lower mean serum gastrin level was observed in the alternate-day group as compared with the daily treated group. CONCLUSION: Alternate-day, long-term treatment with omeprazole may be adequate to maintain remission in patients with reflux esophagitis. This regimen can assure serum gastrin levels within the normal range, thus reducing the potential risk of prolonged, sustained hypergastrinemia and profound hypochlorhydria.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11418787&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Effects of omeprazole and pirenzepine on enterochromaffin-like cells and parietal cells in rat stomach.

Tari A, Kuruhara Y, Yonei Y, Yamauchi R, Okahara S, Sumii K, Kajiyama G.

Department of Internal Medicine, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Japan.

PURPOSE: The purpose of this study was to investigate the mechanism of the regulation of histamine synthesis in enterochromaffin-like cells, chemically and structurally, by treatment with omeprazole and pirenzepine. METHODS: The ultrastructures of enterochromaffin-like cells and parietal cells were examined in rats treated with oral omeprazole (20 mg/kg) or intraperitoneal pirenzepine (1 mg/kg) administration. Serum gastrin concentrations, mRNA levels of H+-K+-ATPase and histidine decarboxylase, and the fundic concentrations of somatostatin and histamine were determined. RESULTS: Pirenzepine treatment suppressed omeprazole-induced increases in serum gastrin levels and mRNA levels of H+-K+-ATPase and histidine decarboxylase. Pirenzepine also decreased omeprazole-induced increases of histamine concentration in fundic mucosa. Pirenzepine elevated somatostatin mRNA level, previously decreased by omeprazole treatment, in fundic mucosa. In the cytoplasm of enterochromaffin-like cells, omeprazole markedly reduced the numbers of vesicles and granules, but significantly increased their diameters, whereas pirenzepine treatment changed neither of these features. The densities and diameters of both vesicles and granules produced by treatment with omeprazole and pirenzepine were between those produced by treatment with omeprazole alone and pirenzepine alone. CONCLUSIONS: Omeprazole-induced hypergastrinemia and pirenzepine-induced somatostatin synthesis play important roles not only in histamine synthesis but also in ultrastructural changes in enterochromaffin-like cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11428583&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Inhibitor effect of omeprazole in isolated human myometrial smooth muscle.

Yildirim K, Sarioglu Y, Kaya T, Cetin A, Yildirim S.

Department of Pharmacology, Cumhuriyet University Faculty of Medicine, Sivas, Turkey.

The aim of the present study was to investigate the effect of omeprazole, an H+-K+-ATPase inhibitor, in myometrial smooth muscle strips from women undergoing elective caesarean section at term. Isolated myometrial strips taken with informed consent were obtained from eight pregnant women undergoing elective caesarean section at term (not in labour) and mounted in organ baths for recording of isometric tension. We recorded the effect of increasing concentrations of omeprazole on spontaneous and Ca2+-induced contractions of myometrial smooth muscle and on contractions of myometrial smooth muscle pretreated with indomethacin (3 x 10(-6) M) and L-NAME (3 x 10(-5) M). Omeprazole (10(-4)-10(-3) M) decreased the amplitude and frequency of spontaneous contractions in a time- and concentration-dependent manner in all myometrial smooth muscle isolated from pregnant women. The decrease in amplitude of contractions in myometrial smooth muscle reached statistical significance beginning from the concentration of 3 x 10(-4) M. Addition of indomethacin (3 x 10(-6) M) and L-NAME (3 x 10(-5) M) in to the organ baths 30 min before did not change relaxation responses to omeprazole. When 8 mM Ca2+-precontracted in Ca2+-free medium myometrial smooth muscle were exposed to increasing concentrations of omeprazole (10(-5)-10(-3) M), omeprazole produced relaxation responses in a time- and concentration-dependent manner, reaching statistical significance at 10(-4) M. These results show: (1) omeprazole time- and concentration-dependently decreased spontaneous contractile activity in myometrial smooth muscle isolated from pregnant women, (2) omeprazole-induced relaxations was not influenced by indomethacin and N(G)-nitro-L-arginine methyl ester (L-NAME), suggesting that it is not mediated by cyclooxygenase products and nitric oxide, and (3) omeprazole brought about time- and concentration-dependently relaxation of myometrial smooth muscle precontracted by 8 mM Ca2+ in Ca2+-free medium. This effect of omeprazole may be due to blockade of the calcium channels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11459434&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
CYP2C19 genotype related effect of omeprazole on intragastric pH and antimicrobial stability.

Kita T, Tanigawara Y, Aoyama N, Hohda T, Saijoh Y, Komada F, Sakaeda T, Okumura K, Sakai T, Kasuga M.

Department of Hospital Pharmacy, School of Medicine, Kobe University, Japan.

PURPOSE: A combination of proton pump inhibitors and antimicrobials has been applied as an anti-Helicobacter pylori (H. pylori) therapy. Omeprazole, one of the proton pump inhibitors, is metabolized by CYP2C19. which exhibits genetic polymorphism. It was reported previously that the overall anti-H. pylori efficacy can be related to the CYP2C19 genotype. The main aim of the present study was to obtain a rational explanation for the relationship between the overall anti-H. pylori efficacy and the CYP2C19 genotype. METHODS: Six healthy volunteers were classified as extensive metabolizers and poor metabolizers, according to their CYP2C19 genotypes. Plasma concentrations and intragastric pH were monitored prior to and until 24 h after the administration of 20 mg omeprazole. The stability of amoxicillin, clarithromycin, and metronidazole was examined using buffer solutions with monitored intragastric pH, and their remaining percentage in the intragastric space was simulated. RESULTS: The poor metabolizers, classified by the CYP2C19 genotypes, showed the higher effectiveness in anti-H. pylori therapy, via the higher plasma concentration of omeprazole and the higher intragastric pH, and possibly the higher stability of antimicrobials in the higher intragastric pH. CONCLUSIONS: CYP2C19 genotyping is a very useful method to determine the effective and safe dosage regimen including the selection of the dual and triple therapy in anti-H. pylori therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11465416&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Probing CYP2C19 and CYP3A4 activities in Chinese liver microsomes by quantification of 5-hydroxyomeprazole and omeprazole sulphone.

Shu Y, Wang LS, Xiao WM, Wang W, Huang SL, Zhou HH.

Pharmacogenetics Research Institute, Hunan Medical University, Changsha 410078, China.

AIM: To develop an analytical method for simultaneous quantification of 5-hydroxyomeprazole (5-OH-OP) and omeprazole sulfone (OPS), and explore whether omeprazole (OP) is an appropriate phenotypic probe for CYP2C19 and CYP3A4 in Chinese liver microsomes. METHODS: OP metabolism in vitro was conducted in Chinese liver microsomes, and the major metabolites 5-OH-OP and OPS were determined using high pressure liquid chromatography (HPLC). Monoclonal antibodies anti-CYP2C8/9/19 and anti-CYP3A4 were employed to conduct inhibition experiments. The protein contents of CYP2C19 and CYP3A4 were quantified using Western blot analysis and densitometric scanning. RESULTS: 5-OH-OP and OPS gave a baseline resolution in the HPLC analysis. The detection limits for both compounds were 0.01 nmol and the recovery (98%-102%) had good precision with relative standard deviation of < 9.5%. Both anti-CYP2C8/9/19 and anti-CYP3A4 had a significant inhibitory effect (P < 0.05) on the 5-OH-OP formation in a substrate concentration-dependent manner, and anti-CYP3A4 alone could almost abolish the formation of OPS (> 87%). At a substrate concentration of 2 mumol/L OP, good correlations were found between OP 5-hydroxylation and S-mephenytoin 4'-hydroxylation activities (r = 0.72, P < 0.01), OP 5-hydroxylation activities and CYP2C19 contents (r = 0.82, P < 0.01), and OP sulfoxidation activities and CYP3A4 contents (r = 0.78, P < 0.01) in Chinese liver microsomes. CONCLUSION: OP metabolism is mediated mainly by CYP2C19 and CYP3A4, and OP can be used to probe CYP2C19 and CYP3A4 activities in Chinese liver microsomes at appropriate substrate concentrations with the HPLC method presently developed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11501187&dopt=Abstract omeprozole Prilosec