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PubMed2005

Acid-suppressive efficacy of a reduced dosage of rabeprazole: comparison of 10 mg twice daily rabeprazole with 20 mg twice daily rabeprazole, 30 mg twice daily lansoprazole, and 20 mg twice daily omeprazole by 24-hr intragastric pH-metry.

Rabeprazole achieves more potent acid suppression than other proton pump inhibitors. Therefore it is administered at reduced as well as high dosages in eradication therapy for Helicobacter pylori; however, there is incomplete assessment of the efficacy of a reduced dosage of rabeprazole as might be employed in therapy. In this study, we evaluated acid-suppressive efficacy of a reduced dosage of rabeprazole on day 7 by 24-hr pH-metry in 10 healthy male cytochrome P-450 2C19 extensive metabolizers without Helicobacterpylori infection and compared the results with those of high dosages of rabeprazole, lansoprazole, and omeprazole. Median intragastric pH value, pH >3 holding time ratio (pH>3HT), pH>4HT, pH>5HT, pH>6HT, and pH>7HT for 24 hr with rabeprazole, 10 mg twice daily, were not significantly different from those of rabeprazole, 20 mg twice daily, lansoprazole, 30 mg twice daily, and omeprazole, 20 mg twice daily. In conclusion, for acid-suppressive efficacy, a reduced dosage of rabeprazole is comparable to high dosages of rabeprazole, lansoprazole, and omeprazole.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2005

Rabeprazole is equivalent to omeprazole in the treatment of erosive gastro-oesophageal reflux disease. A randomised, double-blind, comparative study of rabeprazole and omeprazole 20 mg in acute treatment of reflux oesophagitis, followed by a maintenance open-label, low-dose therapy with rabeprazole.

BACKGROUND: Previous studies have shown similar effects of rabeprazole and omeprazole, when used at the same dose in the treatment of reflux oesophagitis. However, such studies have been conducted as superiority studies but interpreted as equivalence ones. AIM: To properly assess the comparative efficacy of rabeprazole and omeprazole in inducing complete endoscopic healing and symptom relief in patients with reflux oesophagitis. METHODS: Patients (n=560) with Savary-Miller grade I-III reflux oesophagitis were randomised in a double-blind, double-dummy fashion to rabeprazole or omeprazole 20 mg once daily for 4-8 weeks. Then, patients endoscopically healed and symptomatically relieved were openly maintained with rabeprazole 10 mg or 2x10 mg once daily (in the event of clinical and/or endoscopic relapse) for a maximum of 48 weeks. RESULTS: After 4-8 weeks of treatment, healing (primary end-point) was observed in 228/233 (97.9%) patients in the rabeprazole group and in 231/237 (97.5%) in the omeprazole one (equivalence effect demonstrated by p<0.0001 at Blackwelder test and an upper confidence limit at 97.5% of 0.023). However, rabeprazole was faster in inducing heartburn relief than omeprazole (2.8+/-0.2 versus 4.7+/-0.5 days of therapy to reach the first day with satisfactory heartburn relief, p=0.0045 at log-rank test). In the maintenance phase, 15.2% of patients had an endoscopic and/or clinical relapse. CONCLUSION: Rabeprazole is equivalent to omeprazole in healing reflux oesophagitis, but shows a faster activity on reflux symptoms in the early treatment phase.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2005

Stereoselective metabolism of rabeprazole-thioether to rabeprazole by human liver microsomes.

OBJECTIVE: Rabeprazole is metabolized mainly non-enzymatically to rabeprazole-thioether. This in vitro study was designed to clarify the stereoselective oxidation mechanism and to identify the enzyme(s) involved in the metabolic breakdown of rabeprazole-thioether to rabeprazole. METHODS: Rabeprazole-thioether was incubated with human liver microsomes and several recombinant cytochrome P450 (CYP) enzymes (CYPs 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4). High-performance liquid chromatography was used for identification and quantification of each rabeprazole enantiomer. RESULTS: The K(m ) and V(max ) values for the formation of (R)-rabeprazole from rabeprazole-thioether in human liver microsomes were 6.6 microM and 92 pmol/min/mg protein, respectively, whereas those for the formation of (S)-rabeprazole were 5.1 microM and 21 pmol/min/mg protein, respectively. CYP3A4 was found to be the major enzyme responsible for(R)- and (S)-rabeprazole formation from rabeprazole-thioether. The intrinsic clearance (V(max ) /K(m )) for the oxidation by CYP3A4 of (R)-rabeprazole was 3.5-fold higher than that for the (S)-enantiomer (81 nl/min/pmol of P450 vs. 23 nl/min/pmol of P450). On the other hand, CYP2C19 and CYP2D6 were the main enzymes catalyzing the formation of desmethylrabeprazole-thioether from rabeprazole-thioether. The mean K(m ) and V(max ) values of desmethylrabeprazole-thioether formation for CYP2C19 were 5.1 microM and 600 pmol/min/nmol of P450, respectively, whereas those for CYP2D6 were 15.1 microM and 736 pmol/min/nmol of P450, respectively. DISCUSSION: Rabeprazole is reduced mainly non-enzymatically to rabeprazole-thioether, which is further stereoselectively re-oxidized by CYP3A4 mainly to (R)-rabeprazole. The difference in the enantioselective disposition of rabeprazole is determined by stereoselectivity in CYP3A4-mediated metabolic conversion from rabeprazole-thioether to rabeprazole.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2005

Comparison of an increased dosage regimen of rabeprazole versus a concomitant dosage regimen of famotidine with rabeprazole for nocturnal gastric acid inhibition in relation to cytochrome P450 2C19 genotypes.

BACKGROUND AND OBJECTIVE: A concomitant dosage regimen of a histamine 2 receptor antagonist with a proton pump inhibitor (PPI) effectively decreases the incidence of nocturnal acid breakthrough, which is one of the problems encountered when acid-related diseases are treated with a PPI alone. We compared the effectiveness of an increased dosage regimen of rabeprazole with that of a concomitant dosage regimen of rabeprazole with famotidine, relative to cytochrome P450 (CYP) 2C19 genotype status, on nocturnal acid inhibition. METHODS: Fifteen Helicobacter pylori-negative volunteers, consisting of 5 homozygous extensive metabolizers (EMs), 6 heterozygous EMs, and 4 poor metabolizers (PMs) of CYP2C19, took 20 mg rabeprazole, 40 mg rabeprazole, and 20 mg rabeprazole plus 20 mg famotidine at bedtime (at 10 PM) for 8 days. The subjects then underwent 24-hour intragastric pH monitoring on day 8. RESULTS: For the 20-mg rabeprazole, 40-mg rabeprazole, and concomitant dosage regimens, the median percent times and ranges when nocturnal intragastric pH values were lower than 4.0 were 78.8% (47.5%-98.0%), 45.3% (29.0%-52.2%), and 15.5% (0.0%-40.8%), respectively, for homozygous EMs; 51.0% (7.0%-91.6%), 41.3% (33.0%-59.0%), and 18.5% (8.4%-31.9%), respectively, for heterozygous EMs; and 4.5% (2.0%-31.2%), 9.5% (0.0%-31.1%), and 9.3% (0.0%-14.7%), respectively, for PMs. Although significant differences in acid inhibition between the different CYP2C19 genotypes were observed when rabeprazole alone was given (P = .016 for 20 mg rabeprazole and P = .023 for 40 mg rabeprazole), such differences were not observed when famotidine was concomitantly given (P = .206). CONCLUSIONS: The combination regimen of famotidine plus rabeprazole is more effective for nocturnal acid inhibition in homozygous and heterozygous EMs than the increased dosage regimen of rabeprazole. This concomitant therapy could be a rescue regimen for patients with nocturnal acid breakthrough refractory to a standard PPI therapy who are likely to be CYP2C19 EMs.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2005

Determination of rabeprazole and its active metabolite, rabeprazole thioether in human plasma by column-switching high-performance liquid chromatography and its application to pharmacokinetic study.

A new sensitive column-switching high-performance liquid chromatographic (HPLC) method with ultraviolet detection was developed for the simultaneous determination of rabeprazole, a proton pump inhibitor, and its active metabolite, rabeprazole thioether in human plasma. Rabeprazole, its thioether metabolite and 5-methyl-2-[(4-(3-methoxypropoxy)-3-methyl pyridin-2-yl) methyl sulfinyl]-1H-benzimidazole, as an internal standard were extracted from 1 ml of plasma using diethyl ether-dichloromethane (9:1, v/v) mixture and the extract was injected into a column I (TSK-PW precolumn, 10 microm, 35 mmx4.6mm I.D.) for clean-up and column II (C18 Grand ODS-80TM TS analytical column, 5 microm, 250 mmx4.6 mm I.D.) for separation. The peak was detected with an ultraviolet detector set at a wavelength of 288 nm, and the total time for chromatographic separation was approximately 25 min. Mean absolute recoveries were 78.0 and 88.3% for rabeprazole and rabeprazole thioether, respectively. Intra- and inter-day coefficient variations were less than 6.5 and 4.5% for rabeprazole, 3.6 and 5.3% for rabeprazole thioether, respectively, at the different concentration ranges. The validated concentration ranges of this method were 1-1000 ng/ml for rabeprazole and 3-500 ng/ml for rabeprazole thioether. The limits of quantification were 1 ng/ml for rabeprazole and 3 ng/ml for rabeprazole thioether. The method was suitable for therapeutic drug monitoring and was applied to pharmacokinetic study in human volunteers.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2000

Rabeprazole for the prevention of recurrent erosive or ulcerative gastro-oesophageal reflux disease. Rabeprazole Study Group.

OBJECTIVES: To evaluate the efficacy and tolerability of rabeprazole 10 mg and 20 mg versus placebo for the prevention of endoscopically demonstrable relapse in patients previously diagnosed with erosive or ulcerative gastro-oesophageal reflux disease (GORD) who had no oesophageal erosions or ulcerations at study entry. The study also assessed the effectiveness of rabeprazole in preventing GORD symptom recurrence and reductions in quality of life. DESIGN/METHODS: The trial used a multicentre, randomized, double-blind, parallel-group design and enrolled 288 male and female outpatients of > or =18 years of age. Patients were assigned to treatment with either rabeprazole 10 mg or 20 mg once daily in the morning (QAM) or placebo and followed for 52 weeks. RESULTS: Both rabeprazole doses were significantly more effective than placebo in preventing endoscopically demonstrable GORD relapse (P<0.001 versus placebo). The cumulative relapse rate for rabeprazole 10 mg at week 52 was 23%; for rabeprazole 20 mg, 14%; and for placebo, 71%. Both rabeprazole doses were also significantly superior to placebo in preventing relapse of heartburn frequency (P<0.001 for all comparisons between rabeprazole and placebo), with no significant differences between the two doses. Rabeprazole was also significantly more effective than placebo in preventing relapse of day-and night-time heartburn severity, maintaining overall patient well-being, and reducing antacid use. Both rabeprazole doses were well tolerated; most treatment-emergent adverse events were mild or moderate. There were no clinically significant changes in clinical laboratory values, thyroid function tests, vital signs, or electrocardiograms. CONCLUSION: Once-daily treatment with rabeprazole 10 mg or 20 mg is effective and well tolerated in preventing relapse of erosive or ulcerative GORD and associated symptoms and maintaining quality of life.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2000

Efficacy of reduced dosage of rabeprazole in PPI/AC therapy for Helicobacter pylori infection: comparison of 20 and 40 mg rabeprazole with 60 mg lansoprazole.

Proton pump inhibitor (PPI)- based triple therapy has been a recent trend for treatment of Helicobacter pylori infection, with the PPI-amoxicillin-clarithromycin (PPI/AC) regimen being one of the most popular. We have reported the effectiveness of PPI/AC regimens in the Japanese population and have demonstrated that the effectiveness of 40 mg rabeprazole, a recently developed PPI, is similar to that of 40 mg of omeprazole and 60 mg of lansoprazole when used in combination with amoxicillin and clarithromycin. In this study, we focused on whether 20 mg of rabeprazole is effective in our patient population by comparing that dosage with 40 mg of rabeprazole and 60 mg of lansoprazole. In all, 308 H. pylori-infected patients [236 men and 72 women; age (mean +/- SEM) 49.3+/-0.6 years] with peptic ulcer disease (N = 270) or nonulcer dyspepsia (N = 38) were randomly assigned to one of three different PPI/AC regimens for seven days: LAC (N = 104), consisting of lansoprazole 30 mg twice a day, amoxicillin 500 mg three times a day, and clarithromycin 200 mg twice a day; RAC (N = 104), consisting of rabeprazole 20 mg twice a day, amoxicillin 500 mg three times a day, and clarithromycin 200 mg twice a day; and the R1/2AC regimen (N = 100), which included rabeprazole 10 mg twice a day, amoxicillin 500 mg three times a day, and clarithromycin 200 mg twice a day. Cure of the infection was determined by the [13C]urea breath test one month after completion of the treatment. Intention-to-treat based and per-protocol based cure rates for the LAC, RAC, and R1/2AC regimens were 82.7 (95% CI, 74-89) and 88.7% (81-94), 85.6 (77-92) and 89.8% (82-95), and 87.0 (79-93) and 89.7% (82-95), respectively. Although adverse effects were reported by 20.3% of the patients, these affected compliance in only five patients in the RAC and LAC regimens and none in the R1/2AC group. Overall complete compliance was achieved in 94.7% of interviewed patients. In conclusion, the effectiveness of the PPI/AC regimen with 20 mg of rabeprazole is comparable with and even safer than that of 40 mg of rabeprazole and 60 mg of lansoprazole in our patient population.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2000

Rabeprazole versus omeprazole in preventing relapse of erosive or ulcerative gastroesophageal reflux disease: a double-blind, multicenter, European trial. The European Rabeprazole Study Group.

Gastroesophageal reflux disease (GERD) is a chronic condition, with 50-80% of patients experiencing recurrence within one year of completing initial treatment. In patients with erosive GERD, proton-pump inhibitors (PPI) provide faster healing and symptom relief than do H2-receptor antagonists and have become the treatment of choice. Rabeprazole is a new PPI with demonstrated efficacy in both the acute and maintenance treatment of erosive GERD. The primary objective was to compare efficacy and tolerability of rabeprazole and omeprazole in preventing relapse of healed erosive GERD. Secondary objectives included comparison of efficacy in preventing GERD relapse symptoms and in maintaining quality of life. In this multicenter, double-blind, parallel-group study, 243 patients with healed erosive GERD were randomised to receive rabeprazole 10 mg once daily in the morning (QAM) (N = 82); rabeprazole 20 mg QAM (N = 78); or omeprazole 20 mg QAM (N = 83). Endoscopies were performed at weeks 13, 26, 39 (if clinically indicated), and 52, or when symptoms suggested recurrence. Corpus biopsies were performed at each endoscopy, and antral biopsies were performed at study entry and exit. Rabeprazole 10 mg and 20 mg QAM were equivalent to omeprazole 20 mg QAM for all efficacy parameters. At week 52, relapse rates in the intent-to-treat populations were 5%, 4%, and 5% for rabeprazole 10 mg and 20 mg and omeprazole 20 mg, respectively. All treatments were well tolerated. In conclusion, both rabeprazole 10 mg and 20 mg QAM are equivalent to omeprazole 20 mg QAM in preventing recurrence of erosive GERD.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1998

Comparison of rabeprazole 20 mg vs. omeprazole 20 mg in the treatment of active gastric ulcer--a European multicentre study. The European Rabeprazole Study Group.

BACKGROUND: Rabeprazole sodium is the newest member of a class of substituted benzimidazole molecules known as proton pump inhibitors. Other proton pump inhibitors have been shown to be effective in healing active, benign gastric ulcers. METHODS: In this randomized, double-blind, multicentre study, conducted at 25 European sites, rabeprazole and omeprazole were compared in patients with active gastric ulcers. Two hundred and twenty-seven patients with active benign gastric ulcer were randomized to receive either rabeprazole 20 mg (n = 113) or omeprazole 20 mg (n = 114) once daily for 3 or 6 weeks, with healing monitored by endoscopy. RESULTS: After 3 weeks, complete healing (ITT analysis) was documented in 58% of patients given rabeprazole and 61% in patients given omeprazole (N.S.). After 6 weeks the healing rates were identical in both groups at 91%. Rabeprazole-treated patients had numerically greater symptom relief at all 12 points of comparison. The differences significantly favoured rabeprazole at week 3 for daytime pain improvement (P = 0.023) and at week 6 for pain frequency (P = 0.006) and complete resolution of night pain (P = 0.022). Both drugs were well-tolerated over the 6-week treatment course. Mean changes from baseline to end-point in fasting serum gastrin were comparable. No significant differences in laboratory parameters were seen. CONCLUSION: In this study, rabeprazole produced healing rates comparable to omeprazole at weeks 3 and 6, but provided more consistent and occasionally significantly superior symptom improvement. Both treatments were well-tolerated.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1998

Rabeprazole in treatment of acid peptic diseases: results of three placebo-controlled dose-response clinical trials in duodenal ulcer, gastric ulcer, and gastroesophageal reflux disease (GERD). The Rabeprazole Study Group.

Rabeprazole, a new proton pump inhibitor, was studied in patients with acid-peptic-related diseases (duodenal ulcer, gastric ulcer, GERD) in three placebo-controlled, double-blind, randomized clinical trials. Men and women over the age of 18 were enrolled if the presence of an active duodenal or gastric ulcer or erosive or ulcerative esophagitis was confirmed on upper gastrointestinal endoscopy. Patients were randomly allocated to either placebo or rabeprazole 20 mg or 40 mg in the duodenal and gastric ulcer protocols or to placebo or rabeprazole 10 mg, 20 mg, or 40 mg in the GERD protocol. All doses of rabeprazole in all three studies were statistically significantly superior to placebo in healing acid-related lesions. There were no treatment differences between the rabeprazole doses in healing active peptic lesions. The incidence of positive [13C]urea breath test for H. pylori was 53% in patients with duodenal or gastric ulcers. H. pylori status was not effected by treatment with rabeprazole.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1999

Double-blind comparison [correction of Double-blind, placebo-controlled comparison] of rabeprazole 20 mg vs. omeprazole 20 mg in the treatment of erosive or ulcerative gastro-oesophageal reflux disease. The European Rabeprazole Study Group.

BACKGROUND: Rabeprazole sodium is the most recent member of a class of substituted benzimidazole molecules known as proton pump inhibitors. Other proton pump inhibitors have been shown to be effective in healing oesophagitis. METHODS: In this randomised, double-blind, multicentre study, conducted at 27 European sites, the efficacy and safety of rabeprazole and omeprazole were compared in patients with erosive or ulcerative gastro-oesophageal reflux disease (GERD).100 patients received rabeprazole 20 mg, and 102 patients omeprazole 20 mg once daily for 4 or 8 weeks, with healing monitored by endoscopy. RESULTS: Overall GERD healing rates observed and evaluated at weeks 4 and 8 were equivalent. Four-week healing rates for rabeprazole and omeprazole were 81%-81% and 92%-94% for 8-week healing. Rabeprazole-treated patients had similar relief of the frequency and intensity of heartburn to those treated with omeprazole. Both drugs were well tolerated over the 8-week treatment period. Mean changes in fasting serum gastrin were comparable. No significant differences in laboratory parameters were seen. Biopsies for argyrophil ECL cell histology at the end-point revealed a similar distributions of hyperplasia grades to those at baseline in both groups. Biopsies of body and antral mucosa for other parameters were similar between treatments for Helicobacter pylori colonization, presence or degree of inflammation, atrophy or intestinal metaplasia at the end-point. CONCLUSION: In this study, GERD healing rates following rabeprazole 20 mg once daily were equivalent to those obtained with omeprazole 20 mg once daily. Both treatments resulted in a comparable relief of the frequency and intensity of heartburn associated with this disease, and both were well tolerated.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2005

Effects of rabeprazole on early symptom relief in gastro-oesophageal reflux disease: the Hellenic Rabeprazole Study Group surveillance study.

BACKGROUND: In controlled clinical trials, rabeprazole effectively improves symptoms and heals oesophageal erosions in patients with gastro-oesophageal reflux disease (GORD). AIM: To examine symptom relief during week 1 of rabeprazole therapy, in addition to GORD healing, in a clinical practice setting. METHODS: In this 8-week, prospective, multicentre, postauthorisation surveillance study conducted in Greece, patients with GORD (intent-to-treat: efficacy, 272; safety, 273) were treated with rabeprazole 20 mg once daily. The primary efficacy end point was the change from baseline in GORD symptom severity on day 1, 2, 3 and 7 using a 5-point Likert scale (1 = no symptoms; 5 = severe symptoms). Oesophageal healing was also evaluated by comparing the results of endoscopic findings at baseline and after 4 and 8 weeks of treatment. RESULTS: On day 1 of treatment, rabeprazole relieved GORD symptoms across all grades of oesophagitis, with statistically significant (p = 0.0001) improvement in heartburn, regurgitation, epigastric pain and dysphagia. Oesophageal healing was achieved in 77% of patients at week 4 and in 90% at week 8 and treatment was well tolerated. CONCLUSIONS: In a clinical practice setting, rabeprazole provided rapid relief of GORD symptoms, confirming results seen in controlled clinical trials.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2003

High-dose rabeprazole-amoxicillin versus rabeprazole-amoxicillin-metronidazole as second-line treatment after failure of the Japanese standard regimen for Helicobacter pylori infection.

BACKGROUND: There is currently no optimal second-line treatment after failure of Helicobacter pylori triple therapy. AIM: To determine effective salvage therapy after failure of lansoprazole-amoxicillin-clarithromycin. METHODS: After failure of lansoprazole-amoxicillin-clarithromycin 123 out-patients were randomized to receive either 2-week rabeprazole (20 mg b.d.) + amoxicillin (1000 mg b.d.) (RA group) or 1-week rabeprazole (10 mg b.d.) + amoxicillin (750 mg twice b.d.) + metronidazole (250 mg b.d.) (RAM group). Eradication was assessed by the 13C-urea breath test. We also evaluated cytochrome p450 (CYP) 2C19 genotype status, determined by polymerase chain reaction - restriction fragment length polymorphism, and susceptibility to clarithromycin and metronidazole. RESULTS: On an intention-to-treat basis, H. pylori infection cure was achieved in 37 of 63 (59%) patients in the RA group and in 49 of 60 (82%) patients in the RAM group. Per protocol-based eradication rates in the RA and RAM groups were 66% (37/56) and 88% (49/56), respectively. In both analytic sets there were significant differences between the treatment groups (P < 0.01 in each). Mild adverse events were observed in eight and five patients from the RA and RAM groups, respectively. Genetic predisposition of CYP2C19 and antibiotic resistance did not influence the treatment outcome either regimen. CONCLUSIONS: The rabeprazole + amoxicillin + metronidazole therapy yielded satisfactory results. In contrast, the cure rate in high-dose rabeprazole + amoxicillin was below an acceptable level.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMedDate not supplied

Latin American open-label study with rabeprazole in patients with functional dyspepsia. Mexican Rabeprazole Investigators Group.

This multicenter, open-label study assessed the clinical efficacy and tolerability of the proton-pump inhibitor rabeprazole 20 mg once daily in 189 patients with functional dyspepsia and normal findings on upper endoscopy. The clinical efficacy rate was 86% after only 4 weeks of treatment, and symptoms remained under control at the end of 4 weeks without treatment. Rabeprazole was well tolerated and was associated with a low incidence (8%) of mild, transient adverse events.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2006

Effects of clarithromycin and verapamil on rabeprazole pharmacokinetics between CYP2C19 genotypes.

OBJECTIVE: Rabeprazole as a proton pump inhibitor (PPI) is mainly reduced to rabeprazole thioether via a nonenzymatic pathway, with minor CYP2C19 and CYP3A4 involvement. The aim of this study was to compare possible effects of clarithromycin and verapamil as inhibitors of CYP3A4 on the pharmacokinetics of rabeprazole among CYP2C19 genotypes. METHODS: A three-way randomized, double-blind, placebo-controlled crossover study was performed. Nineteen volunteers, of whom six were homozygous extensive metabolizers (EMs), eight were heterozygous EMs, and five were poor metabolizers (PMs) for CYP2C19, received three 6-day courses of either daily 800 mg clarithromycin, 240 mg verapamil, or placebo in a randomized fashion, with a single oral dose of 20 mg rabeprazole on day 6 in all cases. Plasma concentrations of rabeprazole and rabeprazole thioether were monitored up to 24 h after the dosing. RESULTS: In the control phase, the AUC(0-infinity) values for rabeprazole and rabeprazole thioether were 1,005+/-366 and 412+/-149 ng.h/ml in homozygous EMs, 1,108+/-340 and 491+/-245 ng.h/ml in heterozygous EMs, and 2,697+/-364 and 2,116+/-373 ng.h/ml in PMs, respectively. There were significant differences (p<0.001) in the AUC(0-infinity) of rabeprazole and rabeprazole thioether among three different CYP2C19 genotypes. In the clarithromycin and verapamil phases, no significant differences were found in the pharmacokinetic parameters of rabeprazole compared with those in the control phase irrespective of CYP2C19 genotypes, whereas the AUC(0-infinity) of rabeprazole thioether was significantly increased 2.8-fold and 2.3-fold in homozygous EMs (p<0.01), 2.0-fold and 2.0-fold in heterozygous EMs (p<0.05), and 1.6-fold and 1.9-fold in PMs (p<0.05), respectively. In each genotype group for CYP2C19, there were no statistical differences in the percent increase in those pharmacokinetic parameters between the clarithromycin and verapamil pretreatment phases. CONCLUSION: The pharmacokinetic parameters of rabeprazole were not altered by clarithromycin or verapamil irrespective of the CYP2C19 genotypes. However, this result shows that both clarithromycin and verapamil significantly influence the disposition of rabeprazole by inhibiting the oxidation of the thioether, since the AUC(0-infinity) of rabeprazole thioether that has no effect on acid secretion increased. Therefore, the pharmacokinetic interactions between rabeprazole and CYP3A4 or P-glycoprotein inhibitors have limited clinical significance.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2006

Different effects of fluvoxamine on rabeprazole pharmacokinetics in relation to CYP2C19 genotype status.

AIMS: Rabeprazole is known to be a substrate of CYP2C19. Our objective was to evaluate the possible effect of an inhibitor of CYP2C19, fluvoxamine, and compare the inhibitory effect of fluvoxamine on the metabolism of rabeprazole between CYP2C19 genotypes. METHODS: A two-way randomized double-blind, placebo-controlled crossover study was performed. Twenty-one volunteers, of whom seven were homozygous extensive metabolizers (EMs), eight were heterozygous EMs and six were poor metabolizers (PMs) for CYP2C19, received two 6-day courses of either fluvoxamine 50 mg or placebo daily in a randomized fashion with a single oral dose of rabeprazole 20 mg on day 6 in all cases. Plasma concentrations of rabeprazole and its metabolite rabeprazole thioether were monitored up to 24 h after dosing. RESULTS: During placebo administration, the mean AUCs(0,infinity) of rabeprazole in homozygous EMs, heterozygous EMs and PMs were 882 (95% CI, 602, 1162) ng ml-1h , 1214 (975, 1453) ng ml-1 h and 2762 (2482, 3042) ng ml-1 h (P<0.001), respectively. Fluvoxamine treatment increased AUC(0,infinity) of rabeprazole and rabeprazole thioether by 2.8-fold (P<0.001) and 5.1-fold (P<0.01) in homozygous EMs, and by 1.7-fold (P<0.01) and 2.6-fold (P<0.01) in heterozygous EMs, and significantly prolonged the elimination half-life of rabeprazole and rabeprazole thioether in homozygous EMs and in heterozygous EMs, whereas no difference in any pharmacokinetic parameters was found in PMs. There was a significant difference in fluvoxamine-mediated percentage increase in AUC(0,infinity) of rabeprazole and rabeprazole thioether between CYP2C19 genotypes. CONCLUSIONS: The present study indicates that there are significant drug interactions between rabeprazole and fluvoxamine in EMs of CYP2C19. It is predominantly involved in rabeprazole and rabeprazole thioether metabolism in EMs. Therefore, CYP2C19 is the key determinant of rabeprazole disposition in EMs.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1999

Rabeprazole: a review of its use in acid-related gastrointestinal disorders.

Rabeprazole is an inhibitor of the gastric proton pump. It causes dose-dependent inhibition of acid secretion and has a more rapid onset of action than omeprazole. Duodenal ulcers healed faster after treatment with rabeprazole 20 or 40 mg/day than placebo or ranitidine 150 mg 4 times daily and at a generally similar rate to omeprazole 20 mg/day in patients with duodenal ulcers; rabeprazole was similar or superior to these agents in relieving symptoms. Rabeprazole 20 and 40 mg/day healed gastric ulcers faster than placebo, and rabeprazole 20 mg/day healed ulcers at a similar healing rate, to omeprazole 20 mg/day in well controlled 6-week studies. Gastric ulcer symptom relief with rabeprazole was similar or superior to that provided by omeprazole or placebo. In 8-week studies in patients with gastro-oesophageal reflux disease (GERD), rabeprazole 10, 20 and 40 mg/day were more effective than placebo, rabeprazole 20 mg/day was more effective than ranitidine 150 mg twice daily, and rabeprazole 20 mg/day was similar in efficacy to omeprazole 20 mg/day. Symptom relief with rabeprazole in 8-week trials in patients with GERD was superior to that provided by placebo, and similar to ranitidine or omeprazole. Rabeprazole was similar to omeprazole and superior to placebo in both maintenance of healing and prevention of symptoms in patients with healed GERD in 1-year studies. One-week triple therapy with rabeprazole 20 mg twice daily plus 2 antibacterial agents achieved > or = 90% Helicobacter pylori eradication, but, as would be expected, a regimen of rabeprazole 20 mg twice daily plus 1 antibacterial agent was less successful. The drug was as effective as omeprazole and lansoprazole as part of triple therapy for H. pylori eradication. Rabeprazole successfully reduced acid output to target levels and prevented further pathological changes in 10 patients with Zollinger-Ellison syndrome. Usual dosages of rabeprazole are 20 mg/day for 4 weeks to treat duodenal ulcers, 6 weeks for gastric ulcers and 8 weeks for GERD, although some patients with duodenal ulcer may respond to a 10 mg/day dosage. For long term maintenance of GERD healing, 10 or 20 mg daily doses are adequate. Patients with hypersecretory states may need individualised dosages starting at 60 mg/day. The drug was well tolerated in clinical trials, with headache, rash, infection, diarrhoea and flu syndrome as the most common adverse events. In conclusion, rabeprazole appears to be a well tolerated proton pump inhibitor with a rapid onset of action and a low potential for drug interactions. The drug may be used to achieve healing and the relief of symptoms of duodenal ulcer, gastric ulcer and GERD, maintain GERD healing, and can form part of effective regimens to eradicate H. pylori.

2-Pyridinylmethylsulfinylbenzimidazoles↗