omeprazole, Prilosec
Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype.

Chang M, Dahl ML, Tybring G, Gotharson E, Bertilsson L.

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

A single oral dose of omeprazole (20 mg) was given orally to 160 healthy Caucasian Swedish subjects and tested as a probe for CYP2C19. The study was nonrandomized and included seven subjects previously classified as poor metabolizers (PM) of S-mephenytoin. The ratio between the plasma concentrations of omeprazole and hydroxyomeprazole (metabolic ratio; MR) was determined by HPLC in a blood sample drawn 3 h after drug intake. In 17 subjects the test was repeated and the MRs of omeprazole on the two occasions were correlated (rs = 0.85; p < 0.0001). There was a significant correlation between the MR of omeprazole and the S/R mephenytoin ratio among 141 subjects, in whom both ratios were determined (rs = 0.63, p < 0.001). All seven PMs of S-mephenytoin had higher MRs of omeprazole (7.1-23.8) than extensive metabolizers (EM) (0.1-4.9). All 160 subjects and another 15 Caucasian Swedish PMs previously phenotyped with mephenytoin were analysed with respect to the presence of the CYP2C19m1 allele by PCR amplification of the intron 4/exon 5 junction followed by Sma I digestion. EMs heterozygous for the CYP2C19m1 gene had MRs of omeprazole and S/R ratios of mephenytoin that were higher than those of subjects who were homozygous for the wild-type allele (p = 0.0001). Nineteen of the 22 PMs were homozygous for the CYP2C19m1 gene. Three were heterozygous for this allele. Thus, 41 of the 44 alleles (93%) of PMs were defective CYP2C19m1. One of the remaining three PM alleles was subsequently found to contain the CYP2C19m2 mutation, which has earlier been shown to be associated with the PM phenotype in Oriental populations. In conclusion, the phenotype determined by omeprazole correlated with that of mephenytoin, and was in good agreement with the genotype.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8747407&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
[Prospective study of erradication of Helicobacter pylori in patients with duodenal ulcer: analysis of antral and gastric body biopsies]

[Article in Spanish]

Portell DP, Figueroa G, Toledo MS, Troncoso M, Acuna R.

Unidad de microbiologia, Universidad de Chile.

Omeprazole may not eradicate Helicobacter pylori from the stomach but rather displace it from the antrum to the stomach body. This fact could interfere with colonization studies in patients receiving the drug. The aim of this study was to assess the presence of Helicobacter pylori, defined as a positive urease test, culture or microscopical examination, in antral and gastric body biopsies in patients receiving treatment with omeprazole. Sixty four paired antral and gastric body biopsies obtained at the end of a 28 day course of omeprazole, 62 obtained four months later, 40 obtained eight months later and 23 obtained 12 months later were analyzed. There was a 92% concordance between antral and gastric body biopsies for the presence of Helicobacter pylori. However, nine of the samples obtained at 28 days (14%) were negative for H pylori in the antrum but positive in the gastric body. It is concluded that for early assessment of Helicobacter pylori eradication after omeprazole treatment, paired biopsies of antrum and gastric body are needed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8762615&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Effect of omeprazole in the treatment of refractory acid-related diseases in childhood: endoscopic healing and twenty-four-hour intragastric acidity.

Kato S, Ebina K, Fujii K, Chiba H, Nakagawa H.

Department of Pediatrics, Sendal City Hospital, Japan.

OBJECTIVE: To determine the clinical efficacy of once-daily treatment with omeprazole in refractory acid-related diseases in children. METHODS: Endoscopic healing and 24-hour intragastric pH values were assessed in 13 patients with refractory reflux esophagitis (n = 5), refractory and/or giant duodenal ulcer (n = 6), or giant gastric ulcer (n = 2). The mean dose of omeprazole was 0.6 mg/kg per day (range, 0.3 to 0.7 mg/kg per day). Pharmacokinetic studies of omeprazole were performed in seven patients. RESULTS: The cumulative healing rates at 2, 4, 6, and 8 weeks of treatment were 46%, 85%, 92%, and 92%, respectively. Esophagitis in one patient did not heal despite increases in doses of up to 1.6 mg/kg per day (40 mg/day). The mean intragastric pH of omeprazole-treated patients was 5.2 (range, 3.0 to 6.6) and mean hydrogenion activity was 1.78 mmol/L (range, 0.01 to 10.42 mmol/L). There was wide interindividual variation in the reduction of gastric acid production. Mean intragastric H+ activity in omeprazole-treated patients was significantly lower than that of control subjects (p < 0.005) and that of patients treated with histamine type 2(H2)-receptor antagonists (p < 0.05). Mean intragastric H+ activity was not significantly correlated to the area under the concentration-time curve of omeprazole. No severe adverse effects were reported during treatment or at follow-up. CONCLUSIONS: Omeprazole has a potent antisecretory effect and is a suitable alternative for short-term treatment of refractory acid-related diseases; a relatively low dose (0.6 mg/kg per day) appears to be optimal in most patients. Unhealed esophagitis at 8 weeks of treatment was considered to be refractory to omeprazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8774516&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Effect of omeprazole on movement of intravenously administered metronidazole into gastric juice and its significance in treatment of Helicobacter pylori.

Veldhuyzen van Zanten SJ, Pollak PT, Kapoor H, Yeung PK.

Division of Gastroenterology, Faculty of Medicine, Dalhousie University, Victoria General Hospital, Halifax, Nova Scotia, Canada.

Four healthy, Helicobacter-negative volunteers were studied to determine the effect of omeprazole on the movement of metronidazole across the gastric mucosa into the gastric lumen. Each received a 500-mg intravenous infusion of metronidazole and repeated serum, and gastric juice samples were obtained concomitantly over an 8-hr study via indwelling intravenous catheter and nasogastric tube. The same protocol was repeated following one week of oral omeprazole 20 mg twice daily. Metronidazole concentrations were measured by high-performance liquid chromatography. The results demonstrated that: metronidazole moves rapidly from serum into gastric juice; omeprazole causes a marked reduction in total metronidazole concentrations in gastric juice, completely accounted for by pH-related shifts in the proportion of ionized metronidazole, but does not alter concentrations of nonionized metronidazole, which remain above the MIC level against H. pylori; and even under conditions where no pH-related drug trapping occurs (pH > 4), concentrations of metronidazole were higher in gastric juice than in serum during most of the study, indicating that a special transport mechanism may be operational. The practical implication of this effect of omeprazole in combination therapy with metronidazole remains to be established.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8794805&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Monitoring of omeprazole treatment in gastro-oesophageal reflux disease.

Hendel J, Hendel L, Hage E, Hendel J, Aggestrup S, Nielsen OH.

Department of Medical Gastroenterology C, Herlev Hospital, University of Copenhagen, Denmark.

OBJECTIVE: To test our standard dosing regimen in omeprazole treatment of gastro-oesophageal reflux disease (GORD) and to determine whether 'non-responders' could be pinpointed. DESIGN: A reverse dose-response examination using increasing doses of omeprazole. The study was conducted as an open consecutive clinical study. Response was measured by 24-h pH-metry, symptoms, endoscopy and histopathology. SETTING: All patients had been referred to one of the partaking departments for evaluation of oesophageal reflux symptoms. PATIENTS: A total of 62 patients were included, 29 with systemic sclerosis and 33 consecutively included patients suffering from idiopathic oesophageal reflux. RESULTS: Approximately one-third of the patients required doses higher than 40 mg of omeprazole/day (up to 140 mg/day) to abolish GOR. No cases of tachyphylaxia or bile-induced oesophagitis were seen in this study. In all patients subjected to dose titration we were able to achieve healing of oesophagitis assessed by symptom scoring, endoscopy and histopathology. No prediction of final dose of omeprazole could be made. CONCLUSION: Four weeks after reaching a dose level of omeprazole that ensured the abolition of GOR, healing of oesophagitis according to endoscopic/histological evaluation was obtained in all patients. Persistent oesophagitis, i.e. bile induced, was not found.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8804867&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Determination of CYP2C19 phenotype in black Americans with omeprazole: correlation with genotype.

Marinac JS, Balian JD, Foxworth JW, Willsie SK, Daus JC, Owen R, Flockhart DA.

Department of Medicine, University of Missouri-Kansas City, School of Medicine 64108, USA.

BACKGROUND: Our objective was to study omeprazole as a single-dose oral probe in the determination of CYP2C19 phenotype in black subjects and to determine the correlation between phenotype and genotype. METHODS: This single-dose, open-label outpatient study was conducted at a community-based, university-affiliated teaching hospital outpatient clinic. Study subjects were 100 healthy, unrelated black adults (age range, 18 to 50 years) who were receiving no medications. Baseline omeprazole and 2-hour postingestion omeprazole and 5'-hydroxyomeprazole concentrations were measured for phenotype determination. Identification of CYP2C19m1 genotypes were performed with use of the polymerase chain reaction. RESULTS: Results were obtained for 28 men and 72 women. Ninety-eight subjects were found to be phenotypically extensive metabolizers and two to be poor metabolizers (one man; one smoker). Genotype determination revealed that the two poor metabolizers of omeprazole were homozygous for a single base pair mutation (m1/m1) in exon 5 of CYP2C19. Twenty-eight of the extensive metabolizers were heterozygous (m1/wt) and the remaining 70 were homozygous (wt/wt). No side effects were reported. CONCLUSIONS: The 2% prevalence rate of poor CYP2C19 metabolizers in this healthy black population residing in the Midwestern United States is similar to that reported in white subjects and in the Shona population of Zimbabwe but much less than in Asian subjects. Omeprazole is a safe and specific probe of the CYP2C19 enzyme system that correlates well with genotype.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8823231&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Ethnic and genetic determinants of omeprazole disposition and effect.

Caraco Y, Lagerstrom PO, Wood AJ.

Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA.

OBJECTIVES: To compare the pharmacokinetics and dynamics of omeprazole in white and Chinese subjects. METHODS: This double-blind two-stage study, performed in the clinical research center of a university hospital, evaluated 15 healthy nonsmoking men (eight white subjects and seven Chinese extensive metabolizers of mephenytoin). Blood samples were obtained over 24 hours after the eighth omeprazole dose (40 mg/day). Omeprazole, omeprazole sulfone, and hydroxyomeprazole pharmacokinetics were calculated from the respective plasma concentration-time curves. Twelve- and 24-hour integrated plasma gastriun (AUCgas12 and AUCgas24) were calculated from the respective plasma gastrin concentrations. A week before the initiation of omeprazole the activities of CYP2D6, CYP2C19, and CYP3A4 were determined by previously established methods. RESULTS: Omeprazole concentrations were significantly lower (mean area under the plasma concentration time curve extrapolated to infinity [AUCO-infinity] +/- SEM; 7.53 +/- 1.21 versus 12.80 +/- 2.13 mumol.hr.L-1, respectively; p < 0.05) and its oral clearance greater (319 +/- 60 versus 183 +/- 35 ml/min, respectively; p < 0.05) in the white subjects than in the Chinese subjects. Omeprazole and omeprazole sulfone AUCO-infinity values were well correlated with the S/R mephenytoin ratio (r = 0.82 and r = 0.84, respectively; p < 0.001) and with urinary 4'-hydroxymephenytoin (r = -0.58 [p < 0.03] and r = -0.52 [p < 0.02], respectively). Fasting gastrin, AUCgas12, and AUCgas24 were significantly greater in the Chinese subjects than in the white subjects (30.0 +/- 6.4 versus 14.4 +/- 1.2 pmol, respectively [p < 0.02]; 661 +/- 114 versus 334 +/- 38 pmol.hr.L-1, respectively [p < 0.002]; and 1414 +/- 228 versus 747 +/- 99 pmol.hr.L-1, respectively [p < 0.004]). In addition, the S/R mephenytoin ratio and omeprazole AUCO-infinity correlated with the extent of omeprazole induced hypergastrinemia. CONCLUSION: The metabolism of omeprazole and the rise in gastrin concentration after its administration is genetically determined and ethnically dependent.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8823233&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Effects of omeprazole and cimetidine on the urinary metabolic ratio of proguanil in healthy volunteers.

Somogyi AA, Reinhard HA, Bochner F.

Department of Clinical and Experimental Pharmacology, University of Adelaide, Australia.

OBJECTIVE: To examine the effects of omeprazole and cimetidine on the urinary recovery and metabolic ratio of proguanil in healthy subjects. METHODS: A metabolic interaction study was conducted in 12 young, healthy extensive metabolisers of proguanil, a CYP2C19 substrate, following a single 100 mg oral dose by analysis of urine collected for 8 hours. RESULTS: Concomitant administration of omeprazole (20 mg), a CYP2C19 substrate, had no significant effect on the urinary recovery of proguanil or cycloguanil, or the ratio of cycloguanil to proguanil [mean 0.76 (95% CI: 0.53 to 0.98) proguanil alone; mean 0.65 (95% CI: 0.40 to 0.89) proguanil plus omeprazole]. In contrast, cimetidine (400 mg), a general CYP inhibitor and renal organic cation secretion inhibitor, decreased the urinary recovery of cycloguanil and reduced the metabolic ratio from a mean of 0.76 to 0.54 (P < 0.01). In 3 poor metabolisers of proguanil, cimetidine had no effect on the proguanil metabolic ratio. CONCLUSION: The concomitant administration of omeprazole or cimetidine will not result in phenocopying extensive metabolisers of proguanil, although cimetidine inhibits the formation of cycloguanil in extensive metabolisers.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8839666&dopt=Abstract omeprozole Prilosec