omeprazole, Prilosec
Interaction of human liver cytochromes P450 in vitro with LY307640, a gastric proton pump inhibitor.

VandenBranden M, Ring BJ, Binkley SN, Wrighton SA.

Department of Drug Metabolism and Disposition, Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.

The interactions in vitro of LY307640 with the cytochromes P450 (P450s) were studied using human liver microsomes, specific inhibitors of the P450s, and cDNA expressed enzymes. The kinetics of formation of the two major oxidative metabolites, desmethyl LY307640 and LY307640 sulfone, were determined using two human liver microsomal samples. The kinetic data indicated that high and low affinity sites were present for the production of both metabolites of LY307640. The Km(apparent) and Vmax(apparent) for desmethyl LY307640 formation by microsomes from human liver E (HL-E) for the high affinity site were 18.8 +/- 4.4 microM and 402 +/- 52 pmol product/min/mg protein. The high affinity site Km(apparent) and Vmax(apparent) for LY307640 sulfone formation by microsomes from HL-E were 4.4 +/- 2.1 microM and 81.8 +/- 18 pmol product/min/mg protein. The rates of desmethyl LY307640 and LY307640 sulfone formation by the high affinity site were determined using 14 human liver microsomal samples characterized for P450 marker catalytic activities and immunoquantified levels of the P450s. Rates of formation of desmethyl LY307640 significantly correlated with the immunoquantified levels of CYP 2C19 and the ability of the microsomes to 4'-hydroxylate S-mephenytoin. LY307640 sulfone formation significantly correlated with the immunoquantified levels of CYP 3A and the ability of the microsomes to 1'-hydroxylate midazolam. Inhibition studies and use of expressed cytochrome P450 systems confirmed the correlation data demonstrating that CYP 2C19 catalyzed the formation of desmethyl LY307640 and CYP 3A and catalyzed LY307640 sulfone formation. Further, LY307640 competitively inhibited S-mephenytoin 4'-hydroxylation and midazolam 1'-hydroxylation as did the structurally related compound, omeprazole. For the inhibition of S-mephenytoin 4'-hydroxylation and midazolam 1'-hydroxylation, LY307640 had higher Ki(apparent) values than that of omeprazole. These studies demonstrate that the high affinity enzymes which catalyze the formation of the desmethyl and sulfone metabolites of LY307640 are, respectively, CYP 2C19 and CYP 3A. In addition, the inhibition data suggest that LY307640 has less potential to inhibit the metabolism of CYP 2C19 substrates compared to omeprazole, and that LY307640 and omeprazole have a similarly low potential to inhibit the metabolism of CYP 3A substrates.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8845864&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
In vitro antibacterial activity of omeprazole and its selectivity for Helicobacter spp. are dependent on incubation conditions.

Sjostrom JE, Fryklund J, Kuhler T, Larsson H.

Department of Cell Biology, Astra Hassle AB, Molndal, Sweden.

Factors affecting the in vitro antibacterial activity of omeprazole were studied. Our data show that 3H-labeled omeprazole covalently bound to Helicobacter pylori and to other gram-negative and gram-positive bacteria. The compound was found to bind to a broad range of proteins in H. pylori, and at pH 5, binding was enhanced 15-fold compared with binding at pH 7. The bactericidal activity correlated to the degree of binding, and at pH 5, a pH at which omeprazole readily converts to the active sulfenamide form, beta-mercaptoethanol, a known scavenger of sulfenamide, and fetal calf serum, to which noncovalent protein binding of omeprazole is known to occur, reduced the level of binding and almost entirely abolished the bactericidal activity. At pH 7 the killing activities of omeprazole and structural analogs (e.g., proton pump inhibitors) were dependent on the time-dependent conversion (half-life) to the corresponding sulfenamide. The bactericidal activity exerted by the sulfenamide form at pH 5 was not specific for the genus Helicobacter. However, in brucella broth at pH 7 with 10% fetal calf serum, only Helicobacter spp. were susceptible to omeprazole, with MBCs in the range of 32 to 64 micrograms/ml, and MBCs for more stable proton pump inhibitors were higher. Wild-type H. pylori and its isogenic urease-deficient mutant were equally susceptible to omeprazole. Thus, the urease is not a lethal target for omeprazole action in H. pylori. In conclusion, the antibacterial activities of omeprazole and analogs are dependent on pH and the composition of the medium used. Thus, at a low pH in buffer, these compounds have a nonselective action, whereas in broth at neutral pH, the mechanism of action is selective for Helicobacter spp.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8851582&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Omeprazole prevents indomethacin-induced gastric ulcers in rabbits.

Lee M, Kallal SM, Feldman M.

University of Texas Health Science Center at San Antonio, Southwestern Medical Center at Dallas, Dallas, Texas, USA.

BACKGROUND: The role of gastric acid in the development of non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcers is unclear. The aim of this study was to determine the effect of the proton pump inhibitor omeprazole on the formation of indomethacin-induced gastric ulcers in a rabbit model. METHODS: Twenty-four rabbits were randomly divided into four groups and treated as follows: vehicle for indomethacin; vehicle for omeprazole; indomethacin (20 mg/kg b.d. subcutaneously for seven doses); and indomethacin plus omeprazole (both at 20 mg/kg b.d. subcutaneously for seven doses). On day 4 (after the seventh injection), rabbits were sacrificed, and gastric mucosal injury and prostaglandin formation were assessed. RESULTS: Subcutaneous administration of 20 mg/kg omeprazole b.d. caused a profound suppression of gastric acidity (i.e. pH above 5.0 continuously). This same dose of omeprazole significantly reduced gastric ulcer formation induced by indomethacin despite significant (> 80%) inhibition of gastric mucosal prostaglandin E2 (PGE2) formation. CONCLUSION: We conclude from these observations that gastric acid plays a critical role in the formation of indomethacin-induced gastric ulcers in rabbits.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8853761&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Prolonged ambulatory pH monitoring in patients with persistent gastroesophageal reflux disease symptoms: testing while on therapy identifies the need for more aggressive anti-reflux therapy.

Katzka DA, Paoletti V, Leite L, Castell DO.

Department of Medicine, Graduate Hospital, Philadelphia, Pennsylvania, USA.

Patients with gastroesophageal reflux disease (GERD) who remain symptomatic despite receiving a moderate dose of a proton pump inhibitor need accurate assessment to determine who will respond to high doses of the drug or even need surgery. AIM: To determine if prolonged ambulatory pH monitoring performed in patients with persistent symptoms potentially due to GERD while on therapy could predict which patients are likely to benefit from more aggressive anti-reflux therapy. METHODS: Ambulatory pH studies were reviewed for 45 patients with continuing reflux-type symptoms while on 20 mg omeprazole b.i.d. Patients were separated by typical symptoms (heartburn) versus atypical symptoms (chest pain, asthma, hoarseness, cough, throat burning) and for degree of symptom association with episodes of reflux during pH monitoring (symptom index). Control of esophageal acid exposure by omeprazole was defined as distal esophageal pH < 4 < 1.6% total time. RESULTS: Of these 45 patients, 14 (31%) had acid reflux that was not controlled by omeprazole 20 mg b.i.d. Thirty-six patients had atypical symptoms of GERD, and 10 of these patients had poorly controlled reflux. Of these 10 patients, only one patient responded to omeprazole 20 mg q.i.d. In the other nine patients, omeprazole at the higher dose controlled the reflux (documented by pH monitor), but symptoms persisted with poor association to reflux. Thus, only one out of 36 patients with atypical symptoms had subsequent improvement in symptoms. Nine patients had persistent, typical GERD symptoms, and five of these patients had poorly controlled GER. The three patients with good symptom correlation and poorly controlled reflux all responded to increased omeprazole whereas the two with poor symptom association did not. One patient with good control of reflux but good correlation of the remaining reflux to persistent symptoms also responded symptomatically to 80 mg of omeprazole. CONCLUSION: By assessing symptom correlation to reflux episodes and control of reflux by therapy, ambulatory pH monitoring performed in patients with persistent symptoms potentially due to reflux while on therapy gives valuable information concerning further treatment strategies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8855731&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Helicobacter pylori does not migrate from the antrum to the corpus in response to omeprazole.

Graham DY, Genta R, Evans DG, Reddy R, Clarridge JE, Olson CA, Edmonds AL, Siepman N.

VAMC, Houston, Texas, USA.

BACKGROUND: Omeprazole is known to have an effect on Helicobacter pylori in vivo. One opinion is that H. pylori "migrates" from the antrum to the corpus in response to omeprazole therapy. METHODS: To determine whether H. pylori migrates in response to omeprazole, we assessed the presence of H. pylori in the antrum and corpus in duodenal ulcer patients receiving omeprazole for 4 wk. Culture and histological examination of antral biopsies (Genta stain) were performed before patients received omeprazole, at the end of therapy, and 4-6 wk later. The end points were presence or absence of H. pylori and the number of H. pylori colonies per biopsy. RESULTS: Seventy-two patients had H. pylori in both the antrum and corpus at entry and 4-6 wk after ending therapy. Three general patterns were prevalent at the end of omeprazole therapy: antrum- and corpus-positive (54%), antrum-negative and corpus-positive (24%), both antrum- and corpus-negative (21%), and one patient had antrum-positive with corpus-negative (1%). Evaluation of the number of colonies per biopsy in those who remained H. pylori-positive in both the antrum and corpus throughout showed that the number of H. pylori decreased in both the antrum and corpus during therapy (507 +/- 60 vs. 225 +/- 51, p < 0.01 and 415 +/- 58 vs. 290 +/- 46 0.1) for antrum and corpus, respectively, and tended to return to pre-therapy levels 4-6 wk later. The number of H. pylori in the corpus also decreased in the antrum-negative and corpus-positive group during therapy with omeprazole (433 +/- 87 vs. 185 +/- 61, p < 0.05). In most of the patients studied, the number of H. pylori in the corpus was less posttreatment than it was pretreatment. The decrease in H. pylori load was also reflected in the development of false-negative urea breath tests. CONCLUSIONS: Omeprazole is detrimental to H. pylori in both the antrum and the corpus; migration from the antrum to the corpus in response to omeprazole is a myth.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8855733&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Diazepam-omeprazole inhibition interaction: an in vitro investigation using human liver microsomes.

Zomorodi K, Houston JB.

Department of Pharmacy, University of Manchester, UK.

1. The metabolism of diazepam to its primary metabolites 3-hydroxydiazepam (3HDZ) and nordiazepam (NDZ) was evaluated in human liver microsomes. The 3HDZ pathway was the major route of metabolism representing 90% of total metabolism with a Vmax/Km ratio of 0.50-7.26 microliters min-1 mg-1 protein. 2. Inhibition of the two metabolic pathways of diazepam by omeprazole was investigated. The NDZ pathway was not affected by omeprazole whilst a Ki of 201 +/- 89 microM was obtained for the 3HDZ pathway (Km/Ki ratio of 3.0 +/- 0.9). 3. Inhibitory effects of omeprazole sulphone on the 3HDZ and NDZ pathways were also investigated. Omeprazole sulphone inhibited both pathways with similar Kis of 121 +/- 45 and 188 +/- 73 microM respectively (Km/Ki ratios of 5.2 +/- 2.3 and 3.3 +/- 1.5 respectively). 4. These in vitro data provide direct evidence for cytochrome P450 inhibition as the mechanism for the well documented diazepam-omeprazole clinical interaction and indicate that omeprazole sulphone, as well as the parent drug, contribute to the inhibition effect.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8864312&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
A prospective study of the effectiveness of low dose omeprazole as initial therapy in Zollinger-Ellison syndrome.

Termanini B, Gibril F, Stewart CA, Weber HC, Jensen RT.

Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892-1804, USA.

BACKGROUND: The proton pump inhibitors (omeprazole and lansoprazole) are the drugs of choice for the medical management of gastric acid hypersecretion in Zollinger-Ellison syndrome (ZES). These drugs are safe for long-term therapy but are acid-labile and high doses are expensive. The recommended starting dose of omeprazole is 60 mg/day. However, it has been shown in recent studies that the maintenance dose of omeprazole could be safely reduced to 20 mg once or twice a day in more than two-thirds of patients with ZES. The purpose of this study is to determine if an initial starting dose of omeprazole 20 mg/day is safe and effective in patients with ZES. METHODS: Forty-nine consecutive patients with ZES being treated with ranitidine for at least 2 weeks were admitted to the NIH. Omeprazole 20 mg was started on day 1 of the admission and ranitidine discontinued 4 h after the first dose. Gastric acid output was measured for 1 h prior to the next omeprazole dose on day 2, then on day 3 if the value was > 10 mmol/h on the previous day. If acid-peptic symptoms developed or the gastric acid output remained > 10 mmol/h on day 3, the patient was considered to have failed omeprazole 20 mg/day initial therapy and the dose titrated daily to achieve adequate control of acid-peptic symptoms and gastric secretion. RESULTS: In 33 of the 49 patients (68%) omeprazole 20 mg/day was successful as initial therapy. Sixteen patients (32%) failed this initial omeprazole dose (eight patients owing to persistent peptic symptoms and eight patients owing to inadequate acid control). The final daily omeprazole dose required in these patients was 40 mg in eight patients (16%), 60 mg in one patient (2%) and 80 mg in seven patients (14%). Basal acid output (BAO) was the only clinical or laboratory feature that was significantly different between the two groups in which low dose initial omeprazole therapy was or was not successful; all patients with basal acid output < 20 mmol/h had a successful outcome. CONCLUSIONS: Because of the need to rapidly control gastric acid hypersecretion owing to the high risk of complications from peptic ulcer disease, patients with ZES should continue to be started on omeprazole 60 mg/day and the dose adjusted by acute titration methods as is currently recommended. After a maintenance dose is established, attempts should be undertaken to reduce the dose to 20 mg/ day once or twice a day. Only the minority of patients with ZES in whom basal acid output is known to be < 20 mmol/h (20% of patients) should be started on a low initial omeprazole dose.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8871445&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
The effect of omeprazole on gastric juice viscosity, pH and bacterial counts.

Goddard AF, Spiller RC.

Division of Gastroenterology, University Hospital, Nottingham, UK.

BACKGROUND: In vitro studies have shown that pH is an important determinant of mucus structure and function, but the relationship in vivo is unclear. Omeprazole increases intragastric pH and also allows bacterial overgrowth. In this study we have assessed the effect of omeprazole on gastric juice viscosity and examined the influence of pH and bacterial overgrowth on the resulting change. METHODS: Gastric juice specific viscosity, pH and total bacterial counts were measured in nine healthy male volunteers before and after omeprazole 20 mg twice daily for 1 week. The effect of incubation at pH 2 and 7 was also determined. Viscosity changes were compared with changes in pH and bacterial counts. RESULTS: Mean viscosity fell (P < 0.05) following treatment, though there was a wide range in viscosity both before and after treatment. The decrease was reproduced by incubation of pre-treatment juice at pH 7 but not pH 2. The fall in viscosity was correlated (P < 0.05) with change pH. CONCLUSION: Omeprazole decreases gastric juice, and hence gastric mucus, viscosity by increasing intragastric pH. This could be important if it allows improved penetration of antimicrobials to Helicobacter pylori within the mucus layer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8871450&dopt=Abstract omeprozole Prilosec