omeprazole, Prilosec
Enantioselective hydroxylation of omeprazole catalyzed by CYP2C19 in Swedish white subjects.

Tybring G, Bottiger Y, Widen J, Bertilsson L.

Department of Medical Laboratory Sciences and Technology, Karolinska Institute, Huddinge University Hospital, Sweden.

Stereoselective disposition of omeprazole and its formed 5-hydroxy metabolite were studied in five poor metabolizers and five extensive metabolizers of S-mephenytoin. After a single oral dose of omeprazole (20 mg), the plasma concentrations of the separate enantiomers of the parent drug and the 5-hydroxy metabolite were determined for 10 hours after drug intake. In poor metabolizers, the area under the plasma concentration versus time curve [AUC(0-8)] of (+)-omeprazole was larger and that of the 5-hydroxy metabolite of this enantiomer was smaller than the AUC(0-8) values in extensive metabolizers (p < 0.001). The mean AUC(0-8) of the (-)-enantiomer of omeprazole was also higher in poor metabolizers than in extensive metabolizers, but only 3.1-fold compared with 7.5-fold for (+)-omeprazole. The rate of formation of the hydroxy metabolite from (-)-omeprazole was low and not significantly different in poor and extensive metabolizers. These results show that (+)-omeprazole is to a major extent hydroxylated by CYP2C19. Also (-)-omeprazole may partly be metabolized by this enzyme but is mainly metabolized by another enzyme, presumably CYP3A4, to the achiral sulfone metabolite. The plasma concentration ratio of omeprazole to 5-hydroxyomeprazole obtained 3 hours after the drug intake has been used to distinguish between extensive and poor metabolizer phenotypes. With use of the ratio between the (+)-enantiomers of the parent drug and the metabolite, a better discrimination between phenotypes was obtained. The ratio between the (-)-enantiomers also separated the phenotypes but was less discriminatory. For the future, measurement of total concentrations will suffice for phenotyping.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9284848&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Effect of enprostil on omeprazole-induced hypergastrinemia and inhibition of gastric acid secretion in peptic ulcer patients.

Tari A, Hamada M, Kamiyasu T, Sumii K, Haruma K, Inoue M, Kishimoto S, Kajiyama G, Walsh JH.

Department of Internal Medicine, Hiroshima Red Cross Hospital, Japan.

This study was performed to examine the effects of additional enprostil administration on hypergastrinemia and gastric acid suppression induced by omeprazole. Serum gastrin concentrations were measured in 10 peptic ulcer patients (six Helicobacter pylori-positive and four Helicobacter pylori-negative patients) before treatment, after two weeks of omeprazole (20 mg/day), and after two weeks of omeprazole and enprostil (50 micrograms/day). The additional acid inhibitory effect of enprostil was evaluated by 24-hr intragastric pH measurements in five healthy Helicobacter pylori-negative volunteers. After omeprazole treatment, the serum gastrin level of Helicobacter pylori-positive patients (3.5-fold of control) was markedly higher than that of Helicobacter pylori-negative patients (1.7-fold of control). Additional treatment with enprostil suppressed serum gastrin levels to 0.4-fold and 0.7-fold of omeprazole treatment levels in Helicobacter pylori-positive and Helicobacter pylori-negative patients, respectively. In healthy volunteers, median pH recorded during the nonmeal daytime interval increased significantly with additional enprostil. Thus, enprostil reduces undesirable omeprazole-induced hypergastrinemia, especially in Helicobacter pylori-positive patients, and effectively suppresses acid secretion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9286243&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Noninvasive assessment of gastric acid secretion in man. Application of electrical impedance tomography (EIT).

Sarker SA, Mahalanabis D, Bardhan PK, Alam NH, Rabbani KS, Kiber A, Hassan M, Islam S, Fuchs GJ, Gyr K.

Clinical Research and Service Centre, International Centre for Diarrhoeal Diseases Research, Dhaka, Bangladesh.

Electrical impedance tomography (EIT) is a tubeless technique that generates tomographic images of gastric resistivity. We investigated the application of EIT to measure gastric acid secretion. Nineteen normal subjects underwent a standard intubation test. Basal acid output (BAO) and stimulated acid output (SAO) (millimoles per hour) were measured before and after pentagastrin, respectively. On a different day, EIT was performed before (basal) and after pentagastrin (stimulated). The changes in impedance over time were measured and the area under the curve (AUC) was calculated. Both the tests were repeated in 13 subjects after omeprazole treatment. As in the intubation test, there was the expected increase in AUC value after pentagastrin (basal vs stimulated; 1.2 +/- 2.8 vs 731 +/- 297, P < 0.0001). A significant fall in acid output and AUC following omeprazole pretreatment was observed (without vs with omeprazole; 20.5 +/- 5.7 vs 0.03 +/- 0.06, P < 0.0001 for intubation test and 731 +/- 297 vs 44 +/- 172, P < 0.0001 for EIT). There was a significant correlation between SAO and the delta AUC with (r = 0.65 P < 0.001) or without (r = 0.95, P < 0.001) omeprazole and in all the experiments (r = 0.87, P < 0.001). This study demonstrates the predictable change of gastric impedance and may be useful as a noninvasive test for measuring gastric acid secretion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9286252&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Omeprazole, a specific gastric secretion inhibitor on oxynticopeptic cells, reduces gizzard erosion in broiler chicks fed with toxic fish meals.

Hinrichsen JP, Neira M, Lopez C, Chiong M, Ocaranza MP, Gallardo R, Rutman M, Blamey J, Lavandero S.

Departamento de Investigacion Desarrollo, INUAL Ltda (Nutricion y Biotecnologia), Santiago, Chile.

The relation between gizzard erosion-black vomit (GE-BV) and gastric secretion is not completely understood. A pharmacological approach to reduce the presence of GE-BV in chicks due to fish meal in diets is also unknown. In this study the use of omeprazole, a H+/K+ ATPase inhibitor, and fish meals of different biotoxicological characteristics, showed that: 1) Omeprazole decreased total gastric acid content, GE scores and severe GE (SGE) cases, in a dose-dependent manner. This reduction was significant at levels higher than 20 mg omeprazole/Kg body weight (BW)/day (p < 0.01). The addition of 50 mg omeprazole/kg BW/day almost completely prevented the incidence of SGE cases and reduced in 50% GE score in chicks (p < 0.01). 2) A significant reduction in specific mortality, near 90%, was also seen with all toxic fish meals when omeprazole (50 mg/Kg BW/day) was added to experimental diets in comparison to control groups. However, no mortality was observed when omeprazole was added to diets containing non-toxic fish meals. 3) In chicks fed with toxic fish meals, addition of different amounts of omeprazole to diets changed the relative weight of proventriculus (p < 0.01) and gizzard (p < 0.05). Maximum effect was obtained with omeprazole concentration higher than 50 mg/Kg BW/day. 4) Omeprazole did not change feed intake in chicks fed with toxic fish meal. However, in some fish meal a reduction on weight gain was observed with the addition of omeprazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9297806&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Effect of omeprazole paste on intragastric pH in clinically normal neonatal foals.

Sanchez LC, Murray MJ, Merritt AM.

Island Whirl Equine Colic Research Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610-0136, USA.

OBJECTIVE: To evaluate the efficacy of omeprazole paste, a commonly used antiulcer drug, on intragastric pH in clinically normal neonatal foals. ANIMALS: 6 clinically normal foals between 5 and 14 days of age. PROCEDURE: Intragastric pH was recorded in each foal by use of a disposable antimony pH electrode with internal reference. Values for intragastric pH were recorded every 4 seconds by use of an ambulatory pH monitor. There were two 24-hour recordings of intragastric pH for each foal, with 24 hours between recordings. Foals were not administered any drugs during the first recording. Foals were administered omeprazole paste (4 mg/kg, PO) 1 hour after the start of the second recording. Mean pH was calculated for each hour of each 24-hour recording session. Hourly mean values were compared between the first and second 24-hour recordings. RESULTS: Complete data were obtained from 4 of 6 foals during the first 24-hour recording and 6 of 6 foals during the second 24-hour recording. Foals had significantly higher mean hourly intragastric pH for hours 2 to 22 following omeprazole administration, compared with corresponding hourly pH values in foals during the first recording. CONCLUSION AND CLINICAL RELEVANCE: Omeprazole paste can effectively increase intragastric pH in clinically normal neonatal foals within 2 hours after oral administration of the first dose and can be administered to neonatal foals at the rate of 4 mg/kg, PO, every 24 hours.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15334835&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Different contributions of cytochrome P450 2C19 and 3A4 in the oxidation of omeprazole by human liver microsomes: effects of contents of these two forms in individual human samples.

Yamazaki H, Inoue K, Shaw PM, Checovich WJ, Guengerich FP, Shimada T.

Osaka Prefectural Institute of Public Health, 3-69 Nakamichi 1-chome, Higashinari-ku, Osaka 537, Japan.

Omeprazole 5-hydroxylation and sulfoxidation activities were determined in liver microsomes of different humans whose levels of individual forms of cytochrome P450 (P450 or CYP) varied. Correlation coefficients between omeprazole 5-hydroxylation activities (when determined at a substrate concentration of 10 microM) and S-mephenytoin 4'-hydroxylation and testosterone 6beta-hydroxylation activities were found to be 0.64 and 0.67, respectively, in liver microsomes of 84 human samples examined. Omeprazole sulfoxidation activities in these human samples were correlated with testosterone 6beta-hydroxylation activities (r = 0. 86). Omeprazole 5-hydroxylation by liver microsomes of a human sample that contained relatively high levels of CYP3A4 and low levels of CYP2C19 were inhibited very significantly by ketoconazole and anti-CYP3A4 antibodies, although a human sample having high in CYP2C19 and low in CYP3A4 was found to be sensitive toward fluvoxamine and anti-CYP2C9 antibodies. Sulfaphenazole (at 100 microM) did not affect the omeprazole 5-hydroxylation and sulfoxidation catalyzed by human liver microsomes. Both recombinant human CYP2C19 and CYP3A4 enzymes had activities for omeprazole 5-hydroxylation, with low Km and high Vmax values for the former enzyme and high Km and low Vmax values for the CYP3A4. These results suggest that contributions of CYP2C19 and CYP3A4 in the omeprazole 5-hydroxylation depend upon the ratio of these two P450 levels in human liver microsomes. Omeprazole 5-hydroxylation activities of different human samples were found to be related to predicted values calculated from the kinetic parameters of recombinant enzymes and the levels of liver microsomal CYP2C19 and CYP3A4 enzymes. Finally, when recombinant human CYP2C19 and CYP3A4 were mixed at levels found in different human samples, relatively similar profiles of omeprazole oxidation by the recombinant and microsomal enzyme systems were determined by analysis of high-performance liquid chromatography. These results suggest that both CYP2C19 and CYP3A4 are involved in the 5-oxidation of omeprazole (at a substrate concentration of 10 microM) in human liver microsomes and that contributions of these P450 enzymes depend on the compositions of CYP2C19 and CYP3A4 in liver.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9353355&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Effect of omeprazole on the bioavailability of unmodified and phospholipid-complexed aspirin in rats.

Giraud MN, Sanduja SK, Felder TB, Illich PA, Dial EJ, Lichtenberger LM.

Department of Integrative Biology, Pharmacology and Physiology, University of Texas-Houston Medical School, Houston 77030, USA.

BACKGROUND: Treatment and prevention of non-steroidal anti-inflammatory drug-induced gastropathy involve the concurrent use of antisecretory drugs. Recently, we have shown that the ability of these drugs to increase the intragastric pH to values > > pKa of NSAIDs compromises their therapeutic activity. In the present study, we evaluated the potential of omeprazole to interfere with the bioavailability of aspirin administered to rats either alone or complexed with the zwitterionic phospholipid, dipalmitoylphosphatidylcholine (DPPC). METHODS: Aspirin or aspirin/DPPC was administered intragastrically to rats pre-dosed with either saline or omeprazole. Concentrations of aspirin and salicylic acid in the blood and the gastric mucosa were assessed by HPLC and the 6-keto-PGF1 alpha gastric mucosal concentration by radioimmunoassay. RESULTS: Gastric absorption of aspirin and its relative bioavailability were reduced by an antisecretory dose of omeprazole; its inhibitory effect on gastric prostaglandin synthesis was consequently attenuated. However, these effects could be partly overcome if aspirin was administered as a complex with DPPC. CONCLUSIONS: These observations suggest that: (i) DPPC increases the lipid solubility and gastric permeability of NSAIDs; and (ii) neutralization of the gastric pH results in a shift of aspirin absorption toward the intestine where it could be degraded to salicylic acid.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9354198&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Inhibition of the sulfoxidation of omeprazole by ketoconazole in poor and extensive metabolizers of S-mephenytoin.

Bottiger Y, Tybring G, Gotharson E, Bertilsson L.

Department of Medical Laboratory Sciences and Technology, Karolinska Institute, Huddinge University Hospital, Sweden.

BACKGROUND: The metabolism of omeprazole includes hydroxylation catalyzed by CYP2C19 and, to a minor extent, sulfoxidation, presumably by CYP3A4. Sulfoxidation may be the predominant pathway in individuals devoid of the genetically determined CYP2C19 activity. Ketoconazole is a known CYP3A4 inhibitor in daily doses from 200 to 400 mg. In this study ketoconazole was used as a probe to investigate the extent to which CYP3A4 is involved in omeprazole metabolism in vivo. METHODS: A single oral 20 mg dose of omeprazole before and after four daily doses of 200, 100, or 50 mg ketoconazole was given to 10 healthy subjects, previously phenotyped as poor or extensive metabolizers of S-mephenytoin. Concentrations of omeprazole, 5-hydroxyomeprazole, omeprazole sulfone, and ketoconazole were analyzed with reversed-phase HPLC methods in plasma samples collected repeatedly for 12 hours after dosing. RESULTS: After intake of 20 mg omeprazole with 0, 50, 100, and 200 mg ketoconazole, mean values for omeprazole sulfone area under the plasma concentration versus time curve from 0 to 6 hours [AUC(0-6)] were 482, 206, 167, and < 100 nmol/L.hr in extensive metabolizers and 3160, 2430, 937, and 534 nmol/L.hr in poor metabolizers, respectively. Mean omeprazole AUC(0-6) increased from 1660 to 2265 nmol/L.hr in extensive metabolizers and from 7715 to 15319 nmol/L.hr in poor metabolizers after intake of 200 mg ketoconazole. CONCLUSIONS: An oral daily dose of 100 to 200 mg ketoconazole is sufficient to provide a marked inhibition of the formation of the omeprazole sulfone in both extensive and poor metabolizers and leads to a doubling of omeprazole levels in poor metabolizers, whereas 50 mg ketoconazole provides only partial inhibition. We concluded that CYP3A4 catalyzes the sulfoxidation of omeprazole and that this is the predominant metabolic pathway of omeprazole in poor metabolizers of S-mephenytoin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9357389&dopt=Abstract omeprozole Prilosec