Journal of Postgraduate Medicine Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India ISSN: 0022-3859 EISSN: 0972-2823 Vol. 48, Num. 1, 2002, pp. 80-81

Journal of Postgraduate Medicine, Vol. 48, Issue 1, 2002 pp. 80-81

Rabeprazole

Desai CA, Samant BD

Department of Pharmacology and Therapeutics, Seth G. S. Medical College and K. E. M. Hospital, Parel, Mumbai - 400 012, India

Code Number: jp02026

Proton pump inhibitors (PPIs) are the drugs of choice in the management of acid peptic disorders and are more effective than H₂ receptor blockers. PPI - based antibacterial therapy regimens are the gold standard for the eradication of Helicobacter pylori (H. pylori)¹ which is an important agent in the pathogenesis of acid-peptic disease.

Chemical Structure and Mechanism of Action

Rabeprazole is a benzimidazole proton pump inhibitor structurally related to omeprazole but differing slightly by virtue of substitutions on the pyridine and benzimidazole rings. It is a partially reversible inhibitor of H⁺K⁺ ATPase which is activated in the acidic lumen of gastric parietal cells.² It is more potent than omeprazole in inhibition of H⁺ K⁺ ATPase activity and acid output³ and has a quicker onset of action than omeprazole and lansoprazole.⁴ Rabeprazole has also been shown to increase the intracellular mucin content in gastric mucosa in rats.⁵ Longterm animal studies have shown potential to cause enterochromaffin cell hyperplasia without causing more severe proliferative changes.⁶ It has shown greater in vitro antimicrobial activity against H. pylori than omeprazole and lansoprazole.⁷ H. pylori urease enzyme is irreversibly inhibited by rabeprazole.⁸ The thioether derivative of rabeprazole has shown synergism with ampicillin in vivo⁹ and also a strong inhibitory action against both the growth and motility of CRHP (clarithromycin_resistant H. pylori).¹⁰

Clinical Studies

In human studies, once daily doses of 5_40 mg inhibited gastric acid secretion in a dose dependent fashion. A once daily dose of 20 mg has consistently achieved profound decreases in 24 hour intragastric acidity in single and repeat dosing studies, in healthy volunteers and patients.¹¹ Considering the reciprocal increases in plasma gastrin and interindividual variations in response, 20 mg appears to be the preferred dose for routine clinical use.¹²

Rabeprazole in the dose of 20 mg/day or 10 mg twice daily has been shown to be as effective as omeprazole and superior to ranitidine in the healing of gastrooesophageal reflux disease. In long term trials, rabeprazole 10 mg/day was similar to omeprazole 20 mg/day and superior to placebo, in both the maintenance of healing and prevention of symptoms in patients with healed gastrooesophageal reflux disease.

Rabeprazole is as effective as omeprazole and lansoprazole when included as part of a triple therapy regimen for the eradication of H. pylori. As monotherapy for peptic ulcer, healing and symptom relief, studies have shown rabeprazole 10-40 mg/day to be superior to placebo or ranitidine and similar in efficacy to omeprazole. Preliminary data suggest that in Zollinger-Ellison Syndrome, rabeprazole 60-120 mg/day can resolve and prevent the recurrence of symptoms and endoscopic lesions associated with this condition.¹³

Pharmacokinetics

Rabeprazole has an oral bioavailability of approximately 52%.¹⁴ It is dose dependently absorbed after oral administration.¹⁵ It undergoes extensive metabolism via nonenzyme metabolism to form major inactive metabolites (a thioether carboxylic acid metabolite and its glucuronide) and also minor metabolism by CYP2C19 and CYP 3 A4 to desmethyl and sulfone metabolites. Plasma t½ is 1 to 2 hours. No significant accumulation occurs during repeated administration.¹⁵ Bioavailability is not influenced by the co-ingestion of either food or antacids.¹⁴ Approximately 90% of a dose is excreted in the urine primarily as metabolites.¹⁶

Dosage adjustment is not required in the elderly, patients with mild to moderate liver dysfunction or in patients with renal dysfunction. Caution should be exercised, however, in patients with severe liver disease.^16,17

No interaction has been reported with theophylline, phenytoin, warfarin or diazepam.¹⁶

Adverse Events

The most common adverse events assigned to rabeprazole have been diarrhoea, headache, rhinitis, nausea, pharyngitis and abdominal pain.¹³ Recently, in a single case report, investigators have associated rabeprazole with acute fulminant hepatitis.¹⁸ As cases of acute hepatitis have been previously reported with other proton pump inhibitors, patients taking rabeprazole who present with symptoms suggestive of liver dysfunction should be fully investigated. Biopsies from patients in studies of up to 2 years in duration demonstrate some hyperplastic changes in enterochromaffin - like cells, but no adenomatoid, dysplastic or neoplastic changes.¹³ Rabeprazole has been well tolerated in short and long term studies of upto 2 years in duration when administered in doses of upto 120 mg/day for the treatment of acid related disorders.¹³

Dosage and Administration

For healing and symptom relief in patients with duodenal ulcers the usual dosage is 20 mg/day for 4 weeks. In benign gastric ulcers, the usual dose is 20 mg/day for 6 weeks. In patients with erosive or ulcerative gastrooesophageal reflux disease, 8 weeks of treatment is successful. A dosage of either 10 or 20 mg/ day can be used to maintain healing in patients who had been previously treated for erosive or ulcerative gastritis. In patients with H. pylori infection, rabeprazole 20 mg/day in addition to two appropriate antibacterial agents for 1 week is effective in achieving eradication.

Patients with Zollinger Ellison Syndrome usually require doses of 60 mg/day although some have required dosages as high as 60 mg twice daily to decrease acid output to target levels.⁹

Conclusion

Rabeprazole is a well-tolerated proton pump inhibitor. It has been shown to be effective in healing, symptom relief and prevention of relapse of peptic ulcers and gastrooesophageal reflux disease and can form part of effective H. pylori eradication regimens. It is an important alternative to H₂ antagonists and an additional treatment option to other proton pump inhibitors in the management of acid related disorders.

Desai CA, Samant BD

Department of Pharmacology and Therapeutics,
Seth G. S. Medical College and K. E. M. Hospital,
Parel, Mumbai - 400 012, India

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