omeprazole, Prilosec
CYP2C19 genotypes and omeprazole metabolism after single and repeated dosing when combined with clarithromycin.

Zhou Q, Yamamoto I, Fukuda T, Ohno M, Sumida A, Azuma J.

Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.

OBJECTIVES: Omeprazole is metabolized mainly by CYP2C19 which has two major mutations (CYP2C19*2 in exon5 and CYP2C19*3 in exon4) associated with the poor metabolizer (PM) phenotype. The aim of this study was to examine the relationship between genetic polymorphism of CYP2C19 and metabolism of omeprazole administrated as a single dose or as repeated-doses, which were in both cases co-administered with clarithromycin. METHODS: Twelve healthy Japanese subjects were typed for CYP2C19 polymorphism. In the single-dose study, plasma levels of omeprazole and its metabolites were measured for 24 h after administration of 20 mg omeprazole and 400 mg clarithromycin to six healthy Japanese subjects. In the repeated-dose study, plasma levels of omeprazole and its metabolites were measured after repeated oral administration of 20 mg omeprazole and 400 mg clarithromycin twice daily for 6 days and then after 20 mg omeprazole and 400 mg clarithromycin once on the 7th day to the other 6 healthy Japanese subjects. RESULTS: In the single-dose study, the areas under the plasma concentration-versus-time curve (AUCs) of omeprazole of homozygotes for the wild-type allele (*1/*1 n = 2), heterozygotes (n = 3) for the CYP2C19*2 (*1/ *2) or for the CYP2C19*3 (*1/*3) and heterozygote (n = 1) for the two defects (*2/*3) were on average 450, 1007 and 6710 ng x h(-1) x ml(-1), respectively. The ratios of AUCs of omeprazole/5-hydroxyomeprazole for *1/*1, *1/*2 or *1/*3 and *2/*3 were 1, 2 and 30, respectively. In the repeated-dose study, the AUCs of omeprazole for * 1/ *1, *1/*2 or *1/*3 and *2/*3 were 4041 (n = 2), 3149 (n = 3) and 6684 (n = 1) ng x h(-1) x ml(-1), respectively. The ratios of AUCs of omeprazole/5-hydroxyomeprazole for *1/*1, * 1/*2 or * 1/*3 and *2/*3 were7, 11 and 30, respectively. In the repeated-dose study, the AUC of omeprazole of * 1/*1 genotypes was nine-fold higher, that of *1/*2 and *1/*3 genotypes was three-fold higher, and the Cmax value of omeprazole was three-fold higher compared with subjects with the same genotype in the single-dose study. However, there were few differences in the AUC and Cmax of omeprazole between the *2/*3 genotype in the single-dose study and the homozygote for the CYP2C19*2 (*2/*2) in the repeated-dose study. CONCLUSION: Subjects with *1/*1, *1/*2 and *1/*3 genotypes in the repeated-dose study had lower CYP2C19 activity than subjects of the same genotype in the single-dose study. The difference in omeprazole metabolism between subjects with different genotypes observed on day 1 seemed to disappear after 7 days of repeated-dose administration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10206083&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Effect of CYP2C19 polymorphism on serum levels of vitamin B12 in patients on long-term omeprazole treatment.

Sagar M, Janczewska I, Ljungdahl A, Bertilsson L, Seensalu R.

Center of Gastroenterology, Departments of Surgery and Medicine, Clinical Research Center, Stockholm, Sweden.

BACKGROUND: The S-mephenytoin hydroxylase is a polymorphic cytochrome P450 (CYP) enzyme, identified as CYP2C19, which catalyses the metabolism of omeprazole and some other drugs. AIM: To determine whether long-term treatment with omeprazole affects serum vitamin B12 levels, and if so to what extent it depends on CYP2C19 activity. METHODS: Serum vitamin B12 levels (pmol/L) were assessed in 179 patients. Genotyping for wild-type (wt) and mutated (mut) CYP2C19 alleles was performed by allele-specific PCR amplification. RESULTS: One-hundred and eleven of the patients received one dose of 20 mg omeprazole. No difference in B12 levels were found between heterozygous (wt/mut) (n = 23) and homozygous (wt/wt) (n = 85) patients (mean +/- s.d., 350 +/- 82 vs. 315 +/- 87 pmol/L, respectively). Three patients were mut/mut, with serum vitamin B12 levels of 303 +/- 50 pmol/L. In the 68 patients on long-term (>1 year) therapy with 20 mg omeprazole daily, serum vitamin B12 levels were lower in the heterozygous (wt/mut) (n = 19) compared to homozygous wt/wt (n = 49) (246 +/- 71 vs. 305 +/- 98 pmol/L, P = 0. 01, respectively). In one patient (mut/mut) who was studied both after a single dose and after long-term (15 months) treatment with omeprazole, serum vitamin B12 decreased from 360 to 178 pmol/L. In the wt/mut, but not in the wt/wt group, serum vitamin B12 levels were significantly lower in patients on long-term therapy compared with those receiving one dose (246 +/- 71 vs. 350 +/- 82 pmol/L, P < 0.0001, respectively). CONCLUSIONS: CYP2C19 polymorphism significantly affected serum vitamin B12 levels in patients on long-term therapy with omeprazole. In the future, genotyping of CYP2C19 may be useful for patients in need of long-term treatment with omeprazole or other proton pump inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10215728&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Synergistic in vitro antimalarial activity of omeprazole and quinine.

Skinner-Adams T, Davis TM.

Department of Medicine, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia 6160, Australia. tskinner cyllene.uwa.edu.au

Previous studies have shown that the proton pump inhibitor omeprazole has antimalarial activity in vitro. The interactions of omeprazole with commonly used antimalarial drugs were assessed in vitro. Omeprazole and quinine combinations were synergistic; however, chloroquine and omeprazole combinations were antagonistic. Artemisinin drugs had additive antimalarial activities with omeprazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10223960&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Retrospective evaluation of the effect of omeprazole on clozapine metabolism.

Mookhoek EJ, Loonen AJ.

Deltabouman Psychiatric Teaching Hospital, PO Box 800, 3170 DZ Poortugaal, The Netherlands. ejmdpz deltabouman.nl

OBJECTIVE: To study the effect of the replacement of omeprazole by pantoprazole on clozapine metabolism in 13 psychiatric patients, who used both clozapine and omeprazole. METHOD: Retrospective study of the medical files. RESULTS: In comparison to smokers, a significant rise of the serum clozapine levels was observed in all non-smoking patients, whilst the daily dose of clozapine remained unchanged. This effect was probably caused by the discontinuation of enzyme induction of the cytochrome P450 enzyme 1A2 by omeprazole in non-smokers, whereas CYP1A2 remained induced in patients who smoked. CONCLUSION: Omeprazole only influenced clozapine metabolism in non-smokers. In none of the patients an adjustment of the clozapine dose was required.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15230368&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Effect of omeprazole on interdigestive gastroduodenal motility of patients with ulcer-like dyspepsia.

Bortolotti M, Brunelli F, Sarti P, Mari C, Miglioli M.

Department of Internal Medicine and Gastroenterology, University of Bologna, Italy.

BACKGROUND/AIMS: As omeprazole, an antisecretory drug, is largely used in the treatment of acid-related diseases, we investigated its effects on the interdigestive gastroduodenal motility of ulcer-like dyspepsia. METHODOLOGY: Gastroduodenal motility was recorded manometrically in 9 patients complaining of ulcer-like dyspepsia with normal gastric emptying at scintigraphy, without ulcerative lesions and H. pylori infection at endoscopy, and without diseases known to affect gut motility (group ULD), and in a group of 9 healthy subjects as control (group C). After a period sufficient to record two consecutive phases III of the migrating motor complex (MMC) in patients of group ULD, omeprazole 20 mg was infused intravenously 30 min after the end of the last duodenal phase III and the recording was continued to the next one. RESULTS: With respect to the control group, the group ULD showed a significantly longer MMC cycle duration, a frequent absence of gastric phases III and a shorter duration of duodenal phases III. Omeprazole administration in group ULD was followed after 18.9 +/- 8.5 min by a typical gastroduodenal phase III and, consequently, the duration of the omeprazole-related cycle was significantly shortened. These omeprazole-related phases III started from the stomach in nearly all cases and showed a significantly longer duration at the duodenal level with respect to the spontaneous ones. CONCLUSIONS: Patients with ulcer-like dyspepsia showed a decrease in frequency and duration of gastroduodenal phases III. The omeprazole intravenous administration induced the anticipated appearance of an apparently normal gastroduodenal phase III, probably by suppressing the inhibitory action of acid secretion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10228866&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Secondary prevention of upper gastrointestinal bleeding associated with maintenance acid-suppressing treatment in patients with peptic ulcer bleed.

Garcia Rodriguez LA, Ruigomez A.

Centro Espanol de Investigacion Farmacoepidemiologica, Madrid, Spain.

We studied the recurrence of upper gastrointestinal bleeding (UGIB) in a cohort of patients who had an episode of peptic ulcer bleed, and we investigated the effect of maintenance treatment with cimetidine, omeprazole, and ranitidine. We identified 952 patients with a hospitalization for an episode of peptic ulcer bleed by searching the General Practice Research Database in the United Kingdom. The mean follow-up time was 33 months. Less than 10% of the cohort presented with a new episode of UGIB. We calculated incidence rates of recurrent UGIB and estimated the relative risk (RR) of UGIB associated with use of the various acid-suppressing drugs. The greatest protection for recurrent UGIB associated with maintenance acid-suppressing treatment was seen with omeprazole (relative risk 0.2; 95% CI, 0.02-1.0). The corresponding estimates with cimetidine and ranitidine were 0.9 (0.3-2.3) and 0.9 (0.5-1.8). Among nonsteroidal anti-inflammatory drug users, concomitant use of omeprazole afforded protection against a new bleed (RR 0.0; 0.0-1.0), and there was a suggestion of a protective effect with misoprostol, 0.4 (0.01-3.2). The degree of lowered risk of recurrent UGIB in patients on omeprazole maintenance therapy compared with cimetidine or ranitidine therapy is comparable with the protection provided through profound reduction of gastric acidity achieved with proton-pump inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10230829&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
The cost-effectiveness of strategies to assess gastroesophageal reflux as an exacerbating factor in asthma.

O'Connor JF, Singer ME, Richter JE.

Center for Swallowing and Esophageal Disorders, Department of Gastroenterology, Cleveland Clinic Foundation, Case Western Reserve University, Ohio 44195, USA.

OBJECTIVES: We sought to evaluate the cost-effectiveness of diagnostic strategies to determine whether or not acid reflux exacerbates asthma, and to identify which asthma response probabilities are most important in a cost-effective workup of this problem. METHODS: We performed a cost-effectiveness analysis, comparing 11 diagnostic strategies to assess the role that acid reflux plays in asthma. Probabilities and costs were derived from the published literature. Average and incremental costs, effectiveness, and cost-effectiveness were calculated for each strategy. Sensitivity analyses were performed. RESULTS: The most cost-effective diagnostic approach is to begin with omeprazole 20 mg/day for 3 months, followed by 24-h pH testing on drug in nonresponders. If 24-h pH testing is positive, increase the omeprazole dose every 3 months until the patient responds or a maximum of 60 mg/day is given. This strategy costs $730 per case correctly diagnosed. When the cost of pH testing exceeds $586 or the cost of omeprazole 20 mg/day is <$53 per month, omeprazole 20 mg/day for 3 months followed by 60 mg/day for the same duration in nonresponders becomes more cost-effective. CONCLUSIONS: Empiric acid reflux suppression, followed by pH testing in nonresponders, is the most cost-effective means of determining whether GERD is aggravating a patient's asthma.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10364010&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Stability-indicating methods for determining omeprazole and octylonium bromide in the presence of their degradation products.

el-Kousy NM, Bebawy LI.

National Organization for Drug Control and Research, Cairo, Egypt.

Four stability-indicating assays were developed for determining omeprazole and octylonium bromide. Omeprazole is photodegraded and estimated in the presence of its degradation products sulphenamide (I) and benzimidazole sulphide (II) by 2 methods. The first method depends on use of first-, second-, and third-derivative spectrophotometry at 290.4, 320.6, and 311.6 nm, respectively. The second method is based on applying the charge-transfer technique with chloranil as pi acceptor to form a complex with omeprazole, the absorbance of which is measured at 377 nm. These methods determine omeprazole in concentration ranges of 5-20 micrograms/mL by first-, second-, and third-derivative spectrophotometry and 10-50 micrograms/mL by charge-transfer complexation with mean accuracies of 99.92 +/- 0.73, 99.71 +/- 1.02, 99.64 +/- 0.66, and 100.24 +/- 0.81%, respectively. Octylonium bromide is determined by a densitometric method using thin-layer chromatography in the presence of its degradation products p-[2-(n-octyoxy)benzoyl]-aminobenzoic acid (III) and diethyl-(2-hydroxyethyl)-methyl ammonium bromide (IV) without any interferences. Alternatively, octylonium bromide is evaluated by a colorimetric method using the acid dye rose bengal. The ion pair formed is extracted in chloroform at pH 4, and its absorbance is measured at 562 nm. These methods determine octylonium bromide in the presence of its degradation products in concentration ranges of 0.1-0.5 microgram/microL by densitometry and 4.5-22.5 micrograms/mL by colorimetry, with mean accuracies of 100.21 +/- 0.93 and 99.73 +/- 0.89%, respectively. The suggested methods were used to determine drugs in bulk powder, laboratory-prepared mixtures, and pharmaceutical dosage forms. Results were compared statistically with those obtained with reference methods.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10367377&dopt=Abstract omeprozole Prilosec