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Rabeprazole
Clinical data
Pronunciation/rəˈbɛprəˌzɔːl/
Trade namesAciphex, Pariet, Rafron, others
AHFS/Drugs.comMonograph
MedlinePlusa699060
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classProton pump inhibitor[2]
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability52%[2]
Protein binding96.3%[3]
MetabolismCYP2C19 and CYP3A4 in the liver[2]
Metabolitesthioether carboyxlic acid metabolite, thioether glucuronide metabolite, sulfone metabolite[3]
Elimination half-life~1 hour[2]
Excretion90% via kidney as metabolites[4][5]
Identifiers
  • (RS)-2-([4-(3-Methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl)-1H-benzo[d]imidazole
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.123.408 Edit this at Wikidata
Chemical and physical data
FormulaC18H21N3O3S
Molar mass359.44 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture[2]
  • CC1=C(C=CN=C1CS(=O)C2=NC3=CC=CC=C3N2)OCCCOC
  • InChI=1S/C18H21N3O3S/c1-13-16(19-9-8-17(13)24-11-5-10-23-2)12-25(22)18-20-14-6-3-4-7-15(14)21-18/h3-4,6-9H,5,10-12H2,1-2H3,(H,20,21) checkY
  • Key:YREYEVIYCVEVJK-UHFFFAOYSA-N checkY
  (verify)

Rabeprazole, sold under the brand name Aciphex, among others, is a medication that decreases stomach acid.[6] It is used to treat peptic ulcer disease, gastroesophageal reflux disease, and excess stomach acid production such as in Zollinger–Ellison syndrome.[6] It may also be used in combination with other medications to treat Helicobacter pylori.[7] Effectiveness is similar to other proton pump inhibitors (PPIs).[8] It is taken by mouth.[6]

Common side effects include constipation, feeling weak, and throat inflammation.[6] Serious side effects may include osteoporosis, low blood magnesium, Clostridioides difficile infection, and pneumonia.[6] Use in pregnancy and breastfeeding is of unclear safety.[1] It works by blocking H+/K+-ATPase in the parietal cells of the stomach.[6]

Rabeprazole was patented in 1986, and approved for medical use in 1997.[9] It is available as a generic medication.[7] In 2017, it was the 288th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[10]

Medical uses

[edit]
Brand-name rabeprazole tablets.
Bottle of rabeprazole 20 mg tablets.

Rabeprazole, like other proton pump inhibitors such as omeprazole, is used for the purposes of gastric acid suppression.[11] This effect is beneficial for the treatment and prevention of conditions in which gastric acid directly worsens symptoms, such as duodenal and gastric ulcers.[11] In the setting of gastroesophageal reflux disease (GERD), whose pathophysiology is characterized by prolonged exposure to gastric acid in the esophagus (often due to changes in stomach and/or esophagus anatomy, such as those induced by abdominal obesity),[12] acid suppression can provide symptomatic relief.[11] Acid suppression is also useful when gastric production of acid is increased, including rare conditions with excess gastric acid secretion (hypersecretory conditions) like Zollinger-Ellison syndrome (ZES), multiple endocrine neoplasia type 1 (MEN-1), and systemic mastocytosis.[11] In an open-label, industry-sponsored, non-controlled study of high-dose rabeprazole for the treatment of ZES and idiopathic gastric acid hypersecretion (IGAH), including patients with MEN-1 and GERD, rabeprazole induced and maintained suppression of basal acid output over a 24 month period.[13] Only one patient withdrew from the study due to an elevation in creatine phosphokinase judged to be possibly due to rabeprazole, while rabeprazole was otherwise well-tolerated in this population.[13] There are no clinical trials to date that have studied the precise use of rabeprazole, or any PPI, for the treatment of acid-related complaints due to systemic mastocytosis, but acid suppressing medications such as PPIs and H2 receptor antagonists are routinely used to counter the histamine-mediated acid secretion found in this disorder.[14]

Rabeprazole is also useful alongside antibiotic therapy for the treatment of the pathogen Helicobacter pylori, which otherwise thrives in acidic environments.[11] In the original studies that gave rise to its approval for the eradication of H. pylori, rabeprazole was studied in combination with amoxicillin and clarithromycin. This triple therapy was studied at the specific doses of rabeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily for 7 days, which is a higher dose of rabeprazole than what is used for the treatment of simple GERD (20 mg once daily). The higher dose is thought to provide more consistent elevation of pH in the stomach, leading to better eradication of H. pylori, congruent with the dosing strategies of other PPIs for this indication.[15] Notably, H. pylori eradication with antibiotics and rabeprazole was also shown to prevent development of second gastric cancer in a randomized trial in high-risk South Korean patients with early stomach cancer treated by endoscopy.[16]

Thus, rabeprazole is US Food and Drug Administration (FDA) approved for the treatment of symptomatic GERD in adolescents and adults, healing duodenal ulcers in adults, eradication of Helicobacter pylori, and pathologic hypersecretory conditions.[6]

Available forms

[edit]

Rabeprazole is available in 10 and 20 mg, delayed-release tablets (pictured below).[6] Rabeprazole-based products, like other proton pump inhibitor products, have to be formulated in delayed-release tablets to protect the active medication from being degraded by the acid of the stomach before being absorbed.[2]

Specific populations

[edit]

Pediatrics

[edit]

Rabeprazole's only pediatric indication is for the treatment of symptomatic GERD in adolescents (12 years-old and up).[6]

Pregnancy

[edit]

The FDA originally labeled rabeprazole as a pregnancy category B drug (meaning that in vivo research failed to demonstrate a fetal hazard, though human studies are lacking),[17] but it was reclassified as a pregnancy category C drug (meaning that in vivo research has shown a fetal hazard, though the benefit of use may outweigh the risk) in 2014.[18][19] This was after the publishing of an in vivo study that detected changes in bone morphology in rats treated with esomeprazole.[20] In these rats, the following observations were noted:[20][21]

  • shortened femurs, decreased width and thickness of cortical bone, decreased thickness of the tibial growth plate, and minimal to mild bone marrow hypocellularity occurred at doses equal to or greater than 3.4 times the daily maximum recommended human dose (MRHD);
  • decreased survival, decreased birth weight, and an increase in neurobehavioral delays occurred at doses equal to or greater than 16.8 times the daily MRHD;
  • physeal dysplasia of the femur occurred at doses equal to or greater than 33.6 times the daily MRHD.

In vivo studies on rabbits with rabeprazole doses of up to 50 mg/kg/day (about 13 times the normal human drug exposure of rabeprazole at 20 mg) failed to show evidence of fetal harm.[20]

Lactation

[edit]

It is expected that rabeprazole will be secreted into human breast milk, though the clinical impact of this is still unknown. Avoiding rabeprazole during breastfeeding confers to lowest possible risk.[11]

Geriatrics

[edit]

Advanced age does not appear to clinically impact rabeprazole's metabolism.[3] However, elevations in the maximum plasma concentration and the total drug exposure (area under the curve, AUC) have occurred.[11]

Japanese ancestry

[edit]

In a study on rabeprazole's pharmacokinetics, the AUC was elevated by approximately 50–60% in men of Japanese ancestry compared to men in the United States.[22] See the pharmacogenetics section below for a pharmacogenetic explanation of these findings.

Kidney or liver problems

[edit]

In people that have kidney or liver problems, these problems do not appear to affect rabeprazole's metabolism in a clinically meaningful way. This includes individuals on dialysis for kidney problems. Severe liver problems like cirrhosis of the liver do affect rabeprazole's elimination half-life, but not to a degree of dangerous accumulation.[3] In a review of patients taking rabeprazole while having end-stage kidney disease and mild-to-moderate severity, chronic compensated cirrhosis of the liver, the alteration in rabeprazole's metabolism was not clinically meaningful.[2]

Contraindications

[edit]

Rabeprazole is contraindicated in the following populations and situations:[6]

  • people with a known hypersensitivity to rabeprazole, substituted benzimidazoles (which are chemically similar to rabeprazole, like omeprazole), or any other component of the capsule formulation (e.g. certain dyes)
  • concurrent use of rilpivirine, a medication used to treat HIV infection

Hypersensitivity

[edit]

Syndrome

[edit]

An allergy to a PPI like rabeprazole may take the form of type I hypersensitivity or delayed hypersensitivity reactions. A selective (pattern C—see below for a discussion of cross-reactivity patterns) type I hypersensitivity reaction to rabeprazole resulting in anaphylaxis has been reported, as well as several whole group hypersentivities.[23]

Cross-reactivity

[edit]

Hypersensitivity to PPIs can take the form of whole group hypersensitivity, pattern A, B, or C. Whole group hypersentivity occurs when a person is cross-reactive to all PPIs; that is, all PPIs will induce the allergy. In pattern A, a person may be allergic to omeprazole, esomeprazole, and pantoprazole, but not to lansoprazole and rabeprazole. This is thought to be due to the structural similarities between omeprazole, esomeprazole, and pantoprazole, contrasted with lansoprazole and rabeprazole. Pattern B is the opposite, reflecting people that are allergic to lansoprazole and rabeprazole, but not to omeprazole, esomeprazole, and pantoprazole. Pattern C, in the context of rabeprazole, would reflect a person that is allergic to only rabeprazole, but not to other PPIs (omeprazole, esomeprazole, pantoprazole, and lansoprazole).[23]

Rilpivirine

[edit]

Rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of HIV, is contraindicated with all PPIs because of their acid-suppressing effect. PPIs suppress acid, thereby raising the pH of (alkalizing) the stomach's contents. Rilpivirine is best absorbed under acidic conditions. Therefore, rabeprazole would be expected to decrease the absorption of rilpivirine, decrease the concentration of rilpivirine in the blood, and possibly lead to therapeutic failure and induce resistance of the HIV virus to rilpivirine and/or cross-resistance with other NNRTIs.[24]

Adverse effects

[edit]

In general, rabeprazole is fairly well tolerated, even with up to five years of continuous use (the duration of follow-up in a pharmacovigilance clinical trial[25]).[2] The side effect profile is similar to that of omeprazole.[3] The side effect profile is similar to that of omeprazole and other commonly used PPIs.[26] The most common side effects include headache, nausea, and diarrhea.[2] Rare side effects include rashes, flu-like symptoms, and infections (including by the gastrointestinal pathogen Clostridioides difficile[27]).[26] Rare instances of rabeprazole-induced liver injury (also known as hepatotoxicity) have been reported. Characteristic proton-pump inhibitor hepatotoxicity occurs within the first 4 weeks of starting the medication.[28]

Gastrin is an endogenous human hormone that stimulates gastric acid secretion and regulating the growth of certain cells in the stomach.[29] Enterochromafin-like (ECL) cells, responsible for stimulating gastric acid secretion by the release of histamine in the stomach, respond to prolonged gastrin exposure by growing and proliferating.[29] Rabeprazole is associated with elevated serum gastrin levels (hypergastrinemia), which occurs through inhibiting the negative feedback of stomach acid on gastrin secretion by G cells in the antrum of the stomach.[29] The elevation in serum gastrin levels are thought to be dependent upon the degree of rabeprazole's CYP2C19 metabolism. Rabeprazole is not as significantly metabolized by CYP2C19 compared to other medications in the same class, like omeprazole.[2] Hypergastrinemia has been posited as a potential source of rabeprazole-induced neuropsychiatric symptoms (e.g. dizziness, numbness, and tremor), though more research is needed to clarify the effect and mechanism.[30]

Prolonged elevated serum gastrin has been shown to cause rat ECL cells to form carcinoid tumors.[29] According to a 2013 meta-analysis of observational studies, the use of acid-suppressing drugs (including PPIs like rabeprazole, but also histamine receptor 2 antagonists) may be associated with the development of gastric cancer.[31] The studies included in the meta-analysis did not differentiate between rabeprazole and other PPIs,[32][33][34][35] so it is unclear if the potential risk may differ across the PPI class.

Acid suppression via rabeprazole can decrease the absorption of vitamin B12 and magnesium, leading to deficiency.[36] A case of rabeprazole-induced iron deficiency anemia has been reported.[37] Theoretically, rabeprazole could induce an iron deficiency anemia by reducing the dietary absorption of iron, which requires acid for bioavailability.[37]

Very serious side effects have been reported in people taking rabeprazole, but there is no direct evidence that rabeprazole definitely caused these side effects.[11] These include Stevens-Johnson syndrome (a serious disease characterized by skin rash and risk of organ failure), serious blood cell abnormalities, coma, and death.[11] Other possible side effects, common to other PPI medications in the same class, include bone fractures due to osteoporosis, serious infections (including Clostridioides difficile), and kidney damage (nephrotoxicity).[36] A rare, though less understood, side effect of the PPI class is the risk of myopathy and rhabdomyolysis, a syndrome of striated muscle destruction.[38]

Osteoporosis and fractures

[edit]

The mechanism of PPI-induced osteoporosis and fractures is unclear, but hypotheses include hypocalcemia and hypomagnesemia, hyperparathyroidism, and B12 deficiency (inducing neurological deficits and subsequent falls).[39] In opposition to the calcium malabsorption hypothesis, rabeprazole prevented reductions in bone mineral density akin to the effect of minodronic acid in a study of gastrectomized rats.[40] Midodronic acid is a bisphosphonate class drug used to prevent fractures in osteoporosis.[41] Unlike midodronic acid, rabeprazole did not affect serum calcium levels, although the attenuation of gastrectomy-induced bone mineral density reduction at the distal end of the femur suggested inhibition of bone resorption by osteoclasts (like a bisphosphonate).[40]

Infection risk

[edit]

PPIs have been associated with an increased risk for pneumonia by meta-analyses[42][43][44] of case-control and cohort studies.[45] One hypothesis for this association is that PPI-induced acid suppression fosters the growth of aerobic bacteria in the stomach, which can be transferred to the lungs by microaspiration, promoting colonization and subsequent pneumonia.[45] Other hypotheses include off-target proton pump inhibition in the lungs, altering the pH of pulmonary mucus in favor of bacterial growth, and direct inhibition of the activity of white blood cells such as neutrophils and natural killer cells.[44] In line with the stomach acid suppression hypothesis for bacterial overgrowth, PPIs have also been associated with Clostridioides difficile infections.[45] However, as these meta-analyses have pooled PPIs together, it is unknown whether the risk of infection differs significantly between rabeprazole and other members of the PPI class.[45] Rabeprazole was identified as the causative agent in a case report of collagenous colitis, inducing chronic, watery diarrhea.[46]

Other enteric, infectious organisms associated with PPI use include Campylobacter and Salmonella.[47] Both pathogens are sensitive to acid;[48] theoretically, as above, acid suppression by PPIs should increase their pathogenicity. It is unclear if the observed association is due to the PPI itself, as one cohort study found that the association could be explained by the demographic factors of patients prescribed PPIs (e.g. concurrent use of immunosuppressant medications, older age, and antibiotic use).[49] In a clinical trial of 255 Japanese patients, the incidence of PPI-associated diarrhea did not differ between rabeprazole, omeprazole, or lansoprazole.[50]

Nephrotoxicity

[edit]

Forms of kidney damage associated with PPIs in one meta-analysis include acute interstitial nephritis (AIN) (insufficient quality evidence), acute kidney injury (AKI) (low grade evidence), chronic kidney disease (CKD) (low grade evidence), and end-stage renal disease (insufficient quality evidence).[51] The first reported case of rabeprazole-induced acute interstital nephritis occurred in a 62 year-old female in Australia, prescribed rabeprazole for complaints of dyspepsia due to suspected GERD.[52] The mechanism for PPI-induced acute interstital nephritis has not been elucidated, though an immune-related hypothesis has been posited on the basis of extra-renal toxicity consistent with an immunologic, hypersensitivity reaction.[52] It has also been posited that incomplete resolution of PPI-induced acute interstitial nephritis could precede acute kidney injury and chronic kidney disease.[51]

[edit]

Cases of progressive muscle weakness, muscle pain, and rhabdomyolysis following administration of PPIs have been reported in the scientific literature.[38] However, the mechanism for these muscle-related adverse events has yet to be established.[38] In one case, rhabdomyolysis developed in a 50 year-old patient 2 weeks after starting both rabeprazole and domperidone, a prokinetic and antiemetic agent,[53] which resolved after discontinuation of both drugs.[38] Per the French imputability method of causality assessment, it was determined that rabeprazole was a "plausible" cause of the rhabdomyolysis, noting that domperidone was started concurrently.[38]

Overdose

[edit]

No signs and symptoms have been reported in overdoses of rabeprazole up to 80 mg, but case examples are limited.[54] Notably, rabeprazole has been used in higher doses for the treatment of hypersecretory conditions like Zollinger-Ellison syndrome (up to 120 mg daily).[54]

Animal experiments with ultra-high doses of rabeprazole have demonstrated lethality through unknown mechanisms. The lethal overdose syndrome in animals is characterized by convulsion and coma.[22]

Interactions

[edit]

Drug-drug interactions

[edit]

Rabeprazole does not interfere with the plasma concentration of drugs that are also metabolized by the same enzymes (i.e. CYP2C19) that it is metabolized by. Therefore, it is not expected to react with CYP2C19 substrates like theophylline, warfarin, diazepam, and phenytoin.[3] However, the acid-suppression effects of rabeprazole, like other PPIs, may interfere with the absorption of drugs that require acid, such as ketoconazole and digoxin.[11]

There is some evidence that omeprazole and esomeprazole, two medications in the same class as rabeprazole, can disturb the conversion of an anticoagulant medication called clopidogrel to its active metabolite. However, because this is thought to be mediated by the effect of omeprazole and esomeprazole on CYP2C19, the enzyme that activates clopidogrel, this drug interaction is not expected to occur as strongly with rabeprazole. However, whether the effect of omeprazole and esomeprazole on clopidogrel's metabolism actually leads to poor clinical outcomes is still a matter of intense debate among healthcare professionals.[2]

Clinically serious drug-drug interactions may involve the acid-suppression effects of rabeprazole. For example, rabeprazole should not be used concomitantly with rilpivirine, an anti-HIV therapy, which requires acid for absorption. Lowered plasma concentrations of rilpivirine could lead to progression of HIV infection. Other drugs that require acid for absorption include antifungal drugs like ketoconazole and itraconazole, digoxin, iron, mycophenolate, and tyrosine kinase inhibitors like erlotinib, dasatinib, and nilotinib.[6] There is no clinically relevant drug interaction between rabeprazole and antacids.[2][22]

Food-drug interactions

[edit]

Food does not affect the amount of rabeprazole that enters the body,[2] but it does delay its onset of effect by about 1.7 hours.[3]

Pharmacology

[edit]

Mechanism of action

[edit]

Once rabeprazole is taken by mouth, the enteric coating of the tablet allows the drug to pass through the stomach intact.[22] Like other PPIs, rabeprazole is absorbed into the blood stream at the site of the proximal small bowel.[55] Rabeprazole's mechanism of action involves crossing from the blood stream into the parietal cells of the stomach, which are the cells that are responsible for secreting hydrochloric acid (HCl).[11] At this point, rabeprazole is inactive.[11] However, rabeprazole is then secreted into the secretory canaliculus of the parietal cells, which is the space from which acid secretion occurs.[11] Here, acid secretion is mediated by the energy-dependent acid pumps, called hydrogen potassium adenosine triphosphatase (H+/K+ ATPase) pumps.[11] These enzymatic pumps have cysteine amino acid residues.[11] After being activated by gastric (stomach) acid to a reactive sulfenamide intermediate,[56] rabeprazole permanently binds the cysteine residues, forming covalent, disulfide bonds.[11] This action fundamentally alters the configuration of the acid pump, thereby inhibiting its activity. Thus, acid can no longer be secreted into the gastric lumen (the empty space of the stomach), and the pH of the stomach increases (decrease in the concentration of hydrogen ions, H+).[11] Due to the permanent inhibition of the individual proton pump that each molecule of rabeprazole has bound to, acid secretion is effectively suppressed until new proton pumps are produced by the parietal cells.[57]

Rabeprazole, like other medications in the same class, cannot inhibit the H+/K+ ATPase pumps found in lysosomes, a cellular organelle that degrades biological molecules, because the pumps found in these organelles lack the cysteine residues involved in rabeprazole's mechanism of action.[2]

A unique feature of rabeprazole's mechanism of action in inhibiting acid secretion involves its activation. The pKa (the pH at which 50% of the drug becomes positively charged) of rabeprazole is around 5.0, meaning that it doesn't take a lot of acid to activate it. While this theoretically translates into a faster onset of action for rabeprazole's acid-inhibiting effect, the clinical implications of this fact have yet to be elucidated.[11] Theoretically, a high pKa should correlate with off-target activation of the PPI (possibly inducing side effects), though the clinical relevance of this has also yet to be elucidated. See Table 1 for a pKa comparison across PPIs.

Proton pump inhibitor pKa[58]
PPI Omeprazole Esomeprazole Lansoprazole Dexlansoprazole Pantoprazole Rabeprazole
pKa 4.13 4.13 4.01 9.35[59] 3.96 4.90

Table 1 | Comparative pKa values across PPIs. Note that the pKa of dexlansoprazole is a calculated value from a different source, which may have used differing methods than the other PPIs studied.

Pharmacokinetics

[edit]

Rabeprazole's bioavailability is approximately 52%, meaning that 52% of orally administered dose is expected to enter systemic circulation (the bloodstream).[11] Once in the blood, rabeprazole is approximately 96.3%[3]-97%[2] bound to plasma proteins. The biological half-life of rabeprazole in humans is approximately one hour.[2] It takes about 3.5 hours for rabeprazole to reach the maximum concentration in human plasma after a single orally administered dose. Oral absorption is independent of the dose administered.[2]

Rabeprazole is extensively metabolized by the liver.[3] 90% of the drug is rendered into metabolites by the liver, which are then excreted by the kidneys.[4] 10% of the dose is excreted in the feces.[2] The drug metabolizing enzymes primarily responsible for rabeprazole's metabolism are CYP2C19 and CYP3A4.[3] However, rabeprazole is mainly metabolized through non-enzymatic reduction to a thioether metabolite.[2] Some of rabeprazole's metabolites include the following: a thioether carboxylic acid metabolite, a thioether glucuronide metabolite, and a sulfone metabolite.[3] The most common metabolites excreted in the urine are the mercapturic acid conjugate and carboxylic acid.[2] A diagram of rabeprazole's phase I metabolism is shown below.[22]

Phase I metabolism of rabeprazole,[22] drawn in ChemSketch.

Pharmacogenetics

[edit]

The effect of rabeprazole may vary based upon the genetics of the individual taking the medication. People may have differences in their capacity to metabolize rabeprazole to an inactive metabolite. This may be mediated through genetic differences in the gene that encodes for the metabolic enzyme CYP2C19. For example, people that are poor CYP2C19 metabolizers (i.e. their version of CYP2C19 is less effective than average) will have trouble metabolizing rabeprazole, allowing the active rabeprazole to stay in the body, where it can exert its effect, longer than intended. Conversely, extensive CYP2C19 metabolizers (i.e. the average metabolic capacity of CYP2C19) will extensively metabolize rabeprazole, as expected. The poor metabolizing CYP2C19 phenotype is found in roughly 3–5% of Caucasian people, and in 17–20% of people of Asian ancestry.[60] In a study on men of Japanese ancestry, this has translated to an average increase of total drug exposure by 50–60% compared to men in the United States.[22]

However, rabeprazole's metabolism is primarily non-enzymatic (it is often inactivated chemically, without the participation of the body's natural drug metabolizing enzymes). Therefore, while a person's CYP2C19 phenotype will affect rabeprazole's metabolism, it is not expected to dramatically affect the efficacy of the medication.[2]

Chemistry

[edit]
3D representation of rabeprazole spinning along an axis.

Rabeprazole is classified as a substituted benzimidazole, like omeprazole, lansoprazole, and pantoprazole.[56] Rabeprazole possess properties of both acids and bases, making it an amphotere.[56] The acid dissociation constant (pKa) of the pyridine nitrogen is about equal to 4.[56]

Synthesis

[edit]
Rabeprazole synthesis diagram.[61][62]

The above synthesis pathway begins with 2,3-dimethypyridine N-oxide (1). Nitration of 2,3-dimethylpyridine N-oxide affords the nitro derivative (the addition of NO2) (2) The newly introduced nitro group is then displaced by the alkoxide from 3-methoxypropanol to yield the corresponding ether (3). Treatment with acetic anhydride results in the Polonovski reaction. Saponification followed by treatment with thionyl chloride then chlorinates the primary alcohol (5). Reaction with benzimidazole-2-thiol (6) followed by oxidation of the resulting thioether to the sulfoxide yields the final product: rabeprazole (8).[61]

Comparative chemistry

[edit]

The chemical structures in Table 2 illustrate the comparative chemistry of rabeprazole among other members of the PPI class. The structures vary by the substitution of side chains on either the benzimidazole or pyridine ring structures. Omeprazole, for example, has a methoxy moiety (CH3O-) on the benzimidazole ring at position 5, whereas pantoprazole has a difluoromethoxy (CHF2O-) chain at position 5. Lansoprazole has a trifluoroethoxy (CF3-CH2-O-) chain on the pyridine ring at position 4, whereas rabeprazole has a methoxypropoxy (CH3-O-(CH2)3-O-) chain at position 4.[23] Esomeprazole and deslansoprazole represent stereoisomers of omeprazole and lansoprazole respectively.[63][64]

PPI Omeprazole Esomeprazole Lansoprazole
Chemical structure
PPI Dexlansoprazole Pantoprazole Rabeprazole
Chemical structure

Table 2 | Comparative chemical structures of commercially available PPIs.

Physiochemical properties

[edit]

Rabeprazole is characterized as a white to yellowish-white solid in its pure form. It is soluble in a number of solvents. Rabeprazole is very soluble in water and methanol, freely soluble in ethanol, chloroform, and ethyl acetate, and is insoluble in ether and n-hexane.[22] It is unstable under humid conditions.[2]

History

[edit]

Rabeprazole was first marketed in Europe in 1998.[2] In 1999, one year later, rabeprazole was approved for use in the United States.[65]

Development

[edit]

Developed by Eisai Medical Research by the research names E3810 and LY307640, the pre-investigational new drug application was submitted on October 28, 1998. The final investigational new drug application was submitted August 6, 1999. On August 19, 1999, rabeprazole was approved in the US for multiple gastrointestinal indications. The approval for the treatment of symptomatic gastroesophageal reflux disease was on February 12, 2002.[15]

Society and culture

[edit]
[edit]

Rabeprazole is approved in the United States[66] and the United Kingdom[67] for prescription use only. Rabeprazole was approved in India in December 2001.[68] It was approved in Japan in 1997, and in all European Union member countries since.[69]

Brand names

[edit]

Rabeprazole has been sold in a number of brand names:[70]

List of trade names for rabeprazole[70]
Alphabet Brand Name
A Acera, Acifix, Acilesol, Aciphex, Acistal, Akirab, Algibra, An Si Fei, Anslag, Antuc, Apt, Aurizol-R
B Bacanero, Barole, Bauzole, Bepra, Bepraz, Berazol, Berizar, Beryx
C Cyra
D Dexicool, Dexpure, Dirab, Domol
E Eurorapi
F Finix, Fodren
G Gastech, Gastrazole, Gastrodine, Gelbra
H Happi, Helirab, Heptadin
I Idizole
J Jelgrad, Ji Nuo
K
L
M Mergium, Monrab
N Neutracaine, Newrabell, Noflux
O Olrite, Ontime, Oppi-R
P Paliell, Paramet, Paricel, Pariet, Pepcia, Pepraz, Ppbest, Praber, Prabex, Prabexol, Prabez, Promto, Puloros
Q
R Rafron, R-Bit, R-Cid, R-PPI, R-Safe, R.P.Zole, Rabby, Rabe, Rabe-G, Rabeact-20, Rabec, Rabeca, Rabecell, Rabecis, Rabecole, Rabecom, Rabecon, Rabee, Rabefine, Rabegen, Rabekind, Rabelex, Rabelinz, Rabelis, Rabeloc, Rabeman, Rabemed, Rabeol, Rabeone, Rabep, Rabepazole, Rabephex, Rabeprazol, Rabeprazole, Rabeprazolo, Rabeprazolum, Rabesec, Rabestad, Rabetac, Rabetome, Rabetra, Rabetune, Rabeum, Rabex, Rabez, Rabez-FR, Rabezol, Rabezole, Rabibit, Rabicent, Rabicid, Rabicip, Rabifar, Rabifast, Rabilect, Rabip, Rabipot, Rabirol, Rabitab, Rabium, Rabiza, Rabizol, Rablet, Rablet-B, Rabon, Raboz, Rabroz, Rabyprex, Ragi, Ralic, Ramprozole, Raneks, Rap, Rapeed, Rapespes, Rapo, Rapoxol, Rasonix, Razid, Razit, Razo, Razodent, Razogard, Rebacip, Redura, Relitaz, Reorab, Reward, Rifcid, Rodesa, Rolant, Roll, Rowet, Rpraz, Rui Bo te, Rulcer
S Setright, Staycool, Stom, Stomeck
T
U Ulceprazol, Ulcerostate
V Value, Veloz
W Wowrab
X Xin Wei An
Y Yu Tian Qing
Z Zibepar, Zolpras, Zulbex
List of trade names for rabeprazole-containing combination products[70]
Generic Combination Brand Name
rabeprazole, amoxicillin, clarithromycin Rabecure, Pylocure
rabeprazole, amoxicillin, metronidazole Rabefine
rabeprazole, diclofenac Drab, Rabin-DFX, Rclonac, Safediclo, Samurai
rabeprazole, domperidone Acera-D, Acistal-D, Adec-R, Algibra-D, Anslag-D, Antuc-DSR, Biorab-DSR, Catrab-DSR, Comvine, Cyclochek, Cyra-D, Dirab-D, Domol-R, Esoga-RD, Gasonil-D, Gastrazole-D, Happi-D, Helirab-D, Kurab-DSR, Lorab-DSR, Neutraflux, Nuloc-D, Olrite-DSR, Parisec-DSR, Pepchek, Pepcia-D, Peraz-D, Ppbest-D, Prazim-RD, Prorab-D, R-Bit-DM, R-Bit-DSR, R-Cid Plus, R-DSR, R-Safe DSR, Rabby-DSR, Rabecis-DSR, Rabecom-D, Rabecon-DSR, Rabee-D, Rabefine-DSR, Rabelex-D, Rabemac-DSR, Rabep-DSR, Rabephex-D, Rabetome-DM, Rabetome-DSR, Rabetune-D, Rabex-D, Rabez-D, Rabi-DSR, Rabibit-D, Rabicent-D, Rabicip-D, Rabifast-DSR, Rabilect-DSR, Rabipot-D, Rabiprime-DSR, Rablet-D, Rabon-D, Rabon-DSR, Rabroz-DSR, Rabter-SR, Raizol-DSR, Rap-D, Rapeed-D, Rapo-DSR, Raz-DSR, Rebilex-DSR, Redoxid, Redura-D, Redura-DSR, Reorab-D, Reorab-DSR, Reward-D, Reward-DSR, Rifcid-D, Rifcid-DSR, Rifkool-DSR, Robilink-D, Rolant-D, Roll-D, Rpraz-D, Rugbi-DM, Rulcer-DSR, Setright-DSR, Sharaz-D, Staycool-DXR, Stomeck-D SR, Ulgo-DSR, Xenorab-DSR, Zolorab-D, Zomitac-DSR, Zorab-D
rabeprazole, itopride Acera-IT, Antuc-IT, Cool Rab-IT, Happi-IT, Itopraz, Itorab, Jeprab-ITO, Pepraz-I, Rabee-ISR, Rabemac-ITR, Rabetome-ISR, Rabez-IT, Rabibit-ISR, Rablet-I, Rablet-IT, Rebilex-ISR, Reorab-IT, Rex-ISR, Rulcer-IT, Veloz-IT, and Zorite
rabeprazole, lafutidine Lafumac Plus
rabeprazole, levosulpiride Happi-L, Lorab-L, Rabekind Plus, Rabicent-L, Rabifast-XL, Rabin-LXR, Rabinta-L, Rabitem-LS, Robiwel-L, Roll-LS, Wokride
rabeprazole, ondansetron Ond-R, Rulcer-ON
rabeprazole, polaprezinc Happi-XT, Rabez-Z
rabeprazole, sodium bicarbonate Pepcia-FF, Raizol

Research

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An alternative formulation of rabeprazole, termed "rabeprazole-ER" (extended release) has been developed. The purpose of the formulation was to increase the half-life of rabeprazole, which normally is very short in humans. Rabeprazole-ER was a 50 mg capsule composed of five non-identical 10 mg tablets that were designed to release rabeprazole at differing intervals throughout the gastrointestinal system. However, because two high quality clinical trials failed to demonstrate a benefit of rabeprazole-ER versus esomeprazole (another common PPI) for healing grade C or D erosive esophagitis, the development of rabeprazole-ER ceased.[55]

References

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Rabeprazole

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Rabeprazole is a (PPI) medication that suppresses secretion by irreversibly inhibiting the H⁺/K⁺-ATPase enzyme in the parietal cells of the lining. It is primarily used to treat acid-related disorders, including (GERD), peptic ulcers, and pathological hypersecretory conditions such as Zollinger-Ellison syndrome, as well as for eradicating Helicobacter pylori infections in combination with antibiotics and to prevent in patients taking nonsteroidal drugs (NSAIDs). First approved by the U.S. (FDA) in August 1999 under the brand name Aciphex, rabeprazole is available as delayed-release tablets or capsules in doses typically ranging from 10 mg to 20 mg, providing rapid and sustained acid suppression with a favorable pharmacokinetic profile compared to earlier PPIs. As a second-generation PPI, rabeprazole demonstrates high (about 52%) and minimal interaction with enzymes, allowing for fewer drug-drug interactions than some predecessors. Its chemical structure, a derivative with the formula C₁₈H₂₁N₃O₃S (molecular weight 359.4 g/mol), enables activation to a sulfenamide form in acidic environments, ensuring targeted inhibition of the . Rabeprazole exhibits the fastest activation among traditional PPIs, with activation half-times of 1.3 minutes at pH 1.2 (compared to 2.0 minutes for lansoprazole, 2.8 minutes for omeprazole, and 4.6 minutes for pantoprazole) and 7.2 minutes at pH 5.1 (compared to 90 minutes for lansoprazole, 84 minutes for omeprazole, and 282 minutes for pantoprazole). This leads to more rapid onset of acid inhibition and greater symptom relief on the first day of treatment compared to omeprazole, lansoprazole, pantoprazole, and esomeprazole. Newer potassium-competitive acid blockers (e.g., vonoprazan) act even faster but are not PPIs. Clinically, it achieves optimal acid control from the first dose, promoting faster healing of erosive and relief from symptoms like and regurgitation in adults and children. While generally well-tolerated, long-term use requires monitoring for potential risks such as hypomagnesemia, bone fractures, or infections due to reduced gastric acidity.

Medical uses

Indications

Rabeprazole, a (PPI), is primarily indicated for conditions involving excessive production, where it suppresses acid secretion to promote and symptom relief. It is approved for the short-term (4 to 8 weeks) of erosive or ulcerative and for maintenance of to prevent relapse (up to 12 months or longer) in adults with (GERD). In adults and adolescents aged 12 years and older, it is also approved for symptomatic GERD without erosions, usually for up to 4 weeks in adults (with an additional course possible if symptoms persist) and up to 8 weeks in adolescents. Rabeprazole is also indicated for the of duodenal ulcers in adults, providing short-term treatment (up to 4 weeks) for and symptomatic relief, with most patients achieving within this period. For maintenance and to reduce the risk of recurrence in duodenal ulcer disease associated with infection, rabeprazole is used in combination with antibiotics such as amoxicillin (1,000 mg twice daily) and (500 mg twice daily) for 7 days. In pathological hypersecretory conditions, including Zollinger-Ellison syndrome, rabeprazole is indicated for long-term acid suppression, with dosing starting at 60 mg once daily and adjustable up to 120 mg per day, often in divided doses for optimal control, and some patients requiring treatment for over a year.

Available forms and administration

Rabeprazole is available in delayed-release oral tablet formulations in strengths of 10 mg and 20 mg, as well as delayed-release sprinkle capsules in 5 mg and 10 mg strengths for patients who have difficulty swallowing tablets. The standard adult dosing regimen is 20 mg once daily for the treatment of and healing of duodenal ulcers, typically for 4 to 8 weeks. For eradication to treat duodenal ulcers, the recommended dose is 20 mg twice daily in combination with appropriate antibiotics for 7 days. In pathological hypersecretory conditions, such as Zollinger-Ellison syndrome, therapy begins at 60 mg once daily, with doses adjusted up to 120 mg per day in divided administrations as needed for symptom control. Rabeprazole is administered orally and can generally be taken without regard to meals, though tablets for duodenal ulcer healing should be taken after the morning meal, and doses for H. pylori eradication should be taken with meals. The delayed-release tablets must be swallowed whole and should not be chewed, crushed, or split to preserve the that protects the drug from stomach acid. For sprinkle capsules, the contents should be opened and sprinkled onto a small amount of soft food (such as ) or liquid (such as ) at or below , then consumed immediately without chewing the granules; the mixture should not be stored. Treatment duration is typically short-term, limited to 4 to 8 weeks for most indications like GERD and duodenal ulcers, to reduce potential long-term risks associated with inhibitors. For maintenance of healed GERD or hypersecretory conditions, longer durations may be used under medical supervision.

Use in specific populations

Rabeprazole is approved for the treatment of (GERD) in pediatric patients aged 1 to 16 years. In children aged 1 to 11 years, the recommended dose using delayed-release sprinkle capsules is 5 mg once daily for those weighing less than 15 kg (with option to increase to 10 mg if inadequate response) and 10 mg once daily for those weighing 15 kg or more, for up to 12 weeks; for adolescents aged 12 to 16 years, the dose is 20 mg once daily. Use is not recommended in infants younger than 1 year due to lack of demonstrated efficacy. In pregnancy, there are no adequate data from human studies on the use of rabeprazole. In animal reproduction studies, oral administration of rabeprazole to rats and rabbits during organogenesis at doses up to 13 and 8 times the human area under the curve (AUC) at the recommended dose, respectively, showed no evidence of harm to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown; all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. Rabeprazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Rabeprazole and its metabolites are excreted into in models, but data on levels are unavailable. Due to the potential for serious adverse reactions in , an alternative drug is preferred, particularly while a newborn or preterm ; if use is necessary, consideration should be given to discontinuing or the drug. No dosage adjustment is required for geriatric patients, though plasma concentrations may be higher due to age-related reductions in hepatic metabolism and renal function. Long-term use of inhibitors like rabeprazole in older adults is associated with an increased risk of fractures, particularly fractures, warranting monitoring in this population. No dosage adjustment is necessary for patients with mild to moderate hepatic or renal impairment. Caution is advised in severe hepatic impairment, as the have not been adequately studied and accumulation may occur. Patients of Japanese ancestry exhibit higher plasma exposure to rabeprazole, with area under the curve (AUC) approximately 50% greater than in Caucasians, attributed to the higher prevalence of poor metabolizer genotypes in this population; this is associated with enhanced acid suppression efficacy, but standard dosing remains appropriate without adjustment.

Contraindications

Rabeprazole is absolutely contraindicated in patients with known to rabeprazole, substituted benzimidazoles, or any component of the formulation, as these reactions can be severe and potentially life-threatening. This precaution extends to individuals with prior allergic responses to related compounds, ensuring avoidance of initiation in at-risk populations. Hypersensitivity reactions to rabeprazole typically present with symptoms such as , urticaria, , , anaphylactic shock, or , and may also involve acute in some cases. is possible with other inhibitors (PPIs), including omeprazole, due to their shared substituted core structure, which can lead to similar immune-mediated responses upon exposure. Such hypersensitivity events are rare, primarily identified through rather than common clinical trials, with an estimated low incidence among PPI users overall. If a reaction occurs during therapy, immediate discontinuation of rabeprazole is required, followed by supportive care such as antihistamines, corticosteroids, or epinephrine as needed for symptom control. Pre-treatment screening for a history of PPI allergy is essential, and in such cases, alternative acid-suppressive therapies like H2-receptor antagonists (e.g., famotidine) should be considered to manage conditions like without risking recurrence.

Concomitant medications

Rabeprazole, as a (PPI), suppresses secretion, which can impair the absorption of certain pH-dependent medications by elevating intragastric pH. This mechanism underlies significant interaction risks with specific antiretrovirals, leading to contraindications or recommendations to avoid co-administration. Co-administration of rabeprazole with rilpivirine, an antiretroviral used in treatment, is contraindicated due to decreased rilpivirine exposure from reduced absorption in the elevated gastric environment. Studies with similar PPIs, such as omeprazole, demonstrate approximately 40% reductions in rilpivirine AUC, C_max, and C_min, potentially resulting in loss of virologic response and development of resistance. For patients requiring acid suppression while on rilpivirine, alternatives such as H2-receptor antagonists (e.g., famotidine) may be used, administered at least 12 hours before or 4 hours after rilpivirine dosing to minimize impact. Rabeprazole should also be avoided with atazanavir or nelfinavir, as the elevated gastric can decrease their systemic exposure and compromise antiviral , although these are not absolute contraindications. Consultation with the respective antiretroviral prescribing information is advised for any necessary dose adjustments or monitoring. Broader considerations for drug interactions are addressed elsewhere.

Safety profile

Common adverse effects

Rabeprazole is generally well-tolerated during short-term use, with common adverse effects occurring in more than 1% of patients and typically being mild in severity. These include headache (2-3%), diarrhea (2%), nausea (1-2%), abdominal pain (1%), and flatulence (1%). These effects usually onset within the first few days of therapy initiation. They often resolve spontaneously with continued treatment as the body adapts or upon discontinuation of the drug. The gastrointestinal adverse effects, such as , , , and , are likely related to the drug's inhibition of secretion, which alters the gastric environment and may affect gut flora or . may stem from similar systemic adjustments or secondary to gastrointestinal disturbances. Most of these common adverse effects do not require medical intervention, and emphasizing their transient nature can help improve adherence to therapy.

Serious adverse effects

Long-term use of rabeprazole, a (PPI), has been linked to an increased risk of and associated fractures, particularly in the , , and spine. A of observational studies reported an approximately 1.4-fold increased risk of among PPI users compared to non-users, with the risk becoming more pronounced after more than one year of therapy. This association is attributed to potential mechanisms such as reduced calcium absorption due to elevated gastric , and clinical guidelines recommend monitoring bone mineral density in at-risk patients, such as the elderly or those with additional risk factors. Rabeprazole use also elevates the risk of certain infections by suppressing , which normally acts as a barrier against pathogens. A indicated a 1.7-fold increased (OR 1.74, 95% CI 1.47-2.07) of difficile-associated diarrhea in PPI users. Similarly, PPI therapy is associated with a higher incidence of , with one reporting a 49% increased risk (OR 1.49, 95% CI 1.16-1.92), particularly in the initial months of treatment. Nephrotoxicity represents another serious concern, with rabeprazole implicated in rare cases of acute (AIN), occurring at an incidence of approximately 0.01% based on population studies. This hypersensitivity reaction can progress to if not promptly addressed, and often requires confirmation, as seen in reported cases of PPI-induced AIN. Prolonged rabeprazole use exceeding three months carries additional risks, including hypomagnesemia, which the U.S. has warned may require magnesium supplementation or drug discontinuation. Long-term therapy is also associated with the development of fundic gland polyps, benign gastric lesions that regress upon PPI cessation. Furthermore, extended use may contribute to through impaired absorption, with one case-control study showing a 65% increased risk after more than two years of PPI exposure. Meta-analyses as of 2025 suggest an elevated risk of gastric cancer with long-term PPI use (pooled RR 1.3–2.9), though causality remains unclear due to potential confounding factors like underlying infection. Recent studies (as of 2025) continue to associate long-term PPI use with these risks, though some analyses question direct causality for fundic gland polyps and gastric cancer.

Overdose

Human experience with rabeprazole overdose is limited, with no reports of large overdoses. Seven cases of accidental overdosage have been documented, with the maximum reported dose being 80 mg, and no associated clinical signs or symptoms were observed in any of these instances. In patients with Zollinger-Ellison syndrome, therapeutic doses up to 120 mg per day have been well tolerated without specific overdose-related symptoms. Animal studies provide insight into potential toxicity at high doses. Single oral doses of 1024 mg/kg were lethal in rats, accompanied by symptoms such as hypoactivity, labored respiration, convulsions, and leading to . Similar lethality occurred in mice at 786 mg/kg with comparable signs, while dogs tolerated 2000 mg/kg without fatality, though exhibiting watery and . There is no specific for rabeprazole overdose. is symptomatic and supportive, including and administration of activated charcoal if ingestion is recent, along with monitoring of electrolytes and renal function. is ineffective due to the drug's extensive protein binding, which prevents ready dialyzability. Prognosis following rabeprazole overdose is excellent with conservative supportive treatment, and no fatalities have been reported in humans.

Interactions

Drug interactions

Rabeprazole, as a (PPI), can affect the absorption of certain drugs that require an acidic gastric environment for optimal . For instance, coadministration with reduces the of by approximately 30%, while similar effects are observed with , necessitating monitoring of levels and potential separation of dosing to mitigate reduced efficacy. In contrast, rabeprazole may increase exposure, with studies showing approximately 29% and 19% increases in maximum concentration (Cmax) and area under the curve (AUC), respectively, after multiple doses; thus, serum levels should be monitored in patients on prolonged therapy. Additionally, the absorption of -dependent drugs such as iron salts and can be decreased due to elevated gastric , requiring clinical monitoring of therapeutic levels and consideration of dosing adjustments or alternatives. Unlike some other PPIs such as omeprazole, rabeprazole exhibits minimal inhibition of , resulting in negligible pharmacokinetic interactions with substrates like , , , and . Clinical studies in healthy subjects confirm no clinically significant changes in exposure to these drugs, so routine monitoring of their levels is not required during rabeprazole therapy. However, isolated reports of increased international normalized ratio (INR) and have been noted with coadministration, though steady-state interactions remain inadequately evaluated in patient populations. Regarding antiplatelet therapy, concomitant use of rabeprazole with clopidogrel may theoretically reduce the antiplatelet effect due to at , but evidence from healthy subject studies shows no clinically meaningful impact on clopidogrel's exposure, and no dose adjustment is necessary. Nonetheless, due to mixed findings across broader PPI data, caution is advised in high-risk cardiovascular patients, with consideration of alternative PPIs or monitoring of platelet function if needed. High-dose methotrexate therapy can lead to elevated and prolonged serum levels when combined with rabeprazole, potentially increasing toxicity risk; therefore, temporary discontinuation of the PPI is recommended during methotrexate administration in affected patients. Rabeprazole may increase exposure to immunosuppressants such as cyclosporine and through potential metabolic inhibition, as indicated by data showing rabeprazole's for cyclosporine metabolism at 62 micromolar—a concentration far exceeding steady-state levels—though is uncertain; close monitoring of immunosuppressant trough levels and possible dose adjustments are advised during coadministration. Rabeprazole interacts with several antiretrovirals by altering gastric and exposure. It is contraindicated with rilpivirine-containing products due to reduced antiviral from impaired absorption. Additionally, rabeprazole decreases exposure to atazanavir and nelfinavir, potentially reducing their , and increases exposure to , potentially increasing toxicity; concomitant use requires careful monitoring of antiretroviral levels, dose adjustments, or consideration of alternatives.

Food interactions

The absorption of rabeprazole is minimally affected by in terms of overall exposure, though the rate of absorption can be delayed. When rabeprazole delayed-release tablets are administered with , the time to reach maximum plasma concentration (Tmax) is increased by approximately 1.7 hours compared to the state, while the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) remain unchanged. In cases involving a high-fat , this delay in Tmax may extend to 4 hours or longer, but the extent of absorption (AUC) and Cmax are not significantly altered, preserving the drug's absolute oral of approximately 52%. This pharmacokinetic profile arises from rabeprazole's , which shields the from degradation by and enables release in the alkaline environment of the for optimal absorption. , particularly high-fat meals, slows gastric emptying and transit through the , thereby postponing the tablet's arrival at the absorption site without compromising total drug uptake. Clinically, these effects have negligible impact on rabeprazole's antisecretory efficacy, as the unchanged AUC ensures consistent acid suppression over time. As a result, rabeprazole may be taken with or without food, eliminating the need for dosing restrictions relative to meals and thereby supporting better patient adherence.

Pharmacology

Mechanism of action

Rabeprazole is a that exerts its therapeutic effect through irreversible inhibition of the H⁺/K⁺-ATPase enzyme, also known as the , located on the secretory canalicular membrane of in the . This enzyme is responsible for the final step in secretion, where it actively transports hydrogen ions (H⁺) from the into the gastric lumen in exchange for ions (K⁺), utilizing ATP as an source. By covalently binding to the , rabeprazole blocks this H⁺ extrusion, thereby suppressing both basal and stimulated production in a dose-dependent manner. As a weakly basic , rabeprazole (with a pKa of approximately 5.0) is preferentially accumulated in the acidic environment of the canaliculi, where the low facilitates its conversion to an active sulfenamide intermediate. This activated form then forms a bond with specific residues on the H⁺/K⁺-ATPase, such as Cys-813, resulting in irreversible inactivation of the enzyme. Unlike some other inhibitors, rabeprazole's higher pKa allows for activation at a less acidic , contributing to its rapid . Among traditional proton pump inhibitors (PPIs), rabeprazole has the fastest activation half-times: at pH 1.2, 1.3 minutes for rabeprazole compared to 2.0 minutes for lansoprazole, 2.8 minutes for omeprazole, and 4.6 minutes for pantoprazole; at pH 5.1, rabeprazole activates in 7.2 minutes compared to 84–282 minutes for the others. This rapid activation leads to quicker acid suppression and symptom relief on day 1 compared to omeprazole, lansoprazole, pantoprazole, and esomeprazole. Note that newer potassium-competitive acid blockers (e.g., vonoprazan) act faster but are not PPIs. The covalent binding ensures a prolonged duration of acid suppression, lasting approximately 24-48 hours until synthesis of new s occurs, independent of plasma drug levels. Rabeprazole demonstrates faster onset compared to omeprazole, achieving near-complete inhibition of the within minutes in isolated gastric vesicle models and full acid suppression within 1-3 days of dosing in clinical settings. This inhibition disrupts the overall gastric acid secretion process, where intracellular H⁺ ions generated via (CO₂ + H₂O ⇌ H₂CO₃ ⇌ H⁺ + HCO₃⁻) cannot be extruded into the lumen to form (HCl) with ions. H++HCO3−→H2CO3→CO2+H2O\mathrm{H}^{+} + \mathrm{HCO}_{3}^{-} \rightarrow \mathrm{H}_{2}\mathrm{CO}_{3} \rightarrow \mathrm{CO}_{2} + \mathrm{H}_{2}\mathrm{O} The blocked acid extrusion prevents this equilibrium from supporting luminal acidification.

Rabeprazole is rapidly absorbed after , exhibiting an absolute of approximately 52% for a 20 mg dose. Peak plasma concentrations are reached within 2 to 5 hours (Tmax). Concomitant administration of antacids does not significantly affect its absorption or plasma concentration profile. The volume of distribution for rabeprazole is 1.6 L/kg, indicating moderate tissue distribution. It is highly bound to plasma proteins, with binding ranging from 96.3% to 97%, primarily to . Rabeprazole undergoes hepatic primarily via the enzymes and , leading to the formation of the thioether metabolite. A significant portion of its also occurs through non-enzymatic pathways, including the formation of the sulfenamide intermediate. The plasma half-life of rabeprazole is 0.8 to 1.8 hours, contributing to its short systemic exposure. Approximately 90% of the dose is excreted via the renal route primarily as metabolites (no unchanged drug recovered), while the remaining approximately 10% is eliminated in , primarily as metabolites. Steady-state plasma concentrations of rabeprazole are achieved after 3 to 4 days of once-daily dosing, with no appreciable accumulation observed under this regimen. The short half-life reflects its , where non-enzymatic conversion to the active sulfenamide results in irreversible binding to the , despite limited plasma persistence.

Pharmacogenetics

Rabeprazole metabolism is partially mediated by the enzyme , and genetic polymorphisms in the significantly influence its and pharmacodynamic effects. The wild-type *1 is associated with extensive metabolism (*1/*1 ), while the *2 (a common loss-of-function variant) leads to intermediate metabolism in heterozygotes (*1/*2) and poor metabolism in homozygotes (*2/*2). Poor metabolizers (*2/*2) represent approximately 3-5% of the Caucasian population and 15-20% of East Asian populations, reflecting higher frequencies of the *2 and *3 loss-of-function alleles in the latter group. In these individuals, systemic exposure to rabeprazole is increased, with area under the curve (AUC) values approximately 1.5- to 2-fold higher than in extensive metabolizers following standard 20 mg doses, leading to enhanced and prolonged suppression. This effect is less pronounced for rabeprazole compared to other inhibitors due to its partial non-enzymatic metabolism pathway. The clinical impact of polymorphisms on rabeprazole efficacy is evident in eradication therapy, where poor metabolizers achieve higher success rates (often near 100% in small cohorts) owing to greater drug exposure and acid inhibition, which supports antibiotic activity. However, guidelines do not recommend routine genotype-based dose adjustments for rabeprazole, as the variability is moderate and standard dosing remains effective across phenotypes; testing may be considered in non-responders to optimize therapy. Population-specific differences further modulate exposure; in Japanese individuals, total rabeprazole AUC is elevated by 50-60% compared to U.S. populations, attributable in part to higher poor metabolizer prevalence and formulation variations. Polymorphisms in other genes, such as (which contributes minimally to rabeprazole clearance) or ABCB1 (encoding , with no established impact on rabeprazole transport), play negligible roles in its pharmacogenetics.

Chemistry

Structure and properties

Rabeprazole sodium is a substituted characterized by a ring attached via a methylsulfinyl linker and a 3-methoxypropoxy on the pyridine moiety. The is C₁₈H₂₀N₃NaO₃S, with a molecular weight of 381.43 g/mol. Its IUPAC name is 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole sodium salt. Rabeprazole sodium appears as a white to slightly yellowish-white solid and exhibits amphoteric properties due to its acidic sulfinyl group and basic . The pKa of the sulfinyl moiety is approximately 5.0, facilitating in mildly acidic environments, while the benzimidazole has a pKa of 13.3. It is very soluble in (approximately 10-15 mg/mL) and , freely soluble in , , and , but insoluble in and n-hexane. Due to its acid lability, rabeprazole sodium is formulated as enteric-coated tablets to protect it from degradation in . It degrades rapidly in acidic media through rearrangement to a sulfenamide , with an of 78 seconds at 1.2, but remains more stable under alkaline conditions. The compound is unstable in humid environments and should be stored below 30°C, protected from moisture, in its original container. Compared to other inhibitors, rabeprazole exhibits less dependence on metabolism than omeprazole, as its clearance is largely nonenzymatic. It has similar potency to in acid inhibition but demonstrates faster activation due to its higher pKa, allowing and reactivity at higher levels.

Synthesis

The synthesis of rabeprazole typically begins with the preparation of the key pyridine derivative, 2-chloromethyl-3-methyl-4-(3-methoxypropoxy)pyridine, which is obtained by chlorination of the corresponding hydroxymethyl compound using thionyl chloride in dichloromethane at room temperature. This chloromethyl pyridine is then reacted with 2-mercaptobenzimidazole in ethanol at 40–50°C in the presence of sodium hydroxide to form the sulfide intermediate, 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]thio]-1H-benzimidazole, in approximately 87% yield. The final step involves selective oxidation of the sulfide to the sulfoxide, rabeprazole, using m-chloroperbenzoic acid in dichloromethane at –40°C under a nitrogen atmosphere, followed by treatment with triethylamine and conversion to the sodium salt with aqueous sodium hydroxide; this yields rabeprazole sodium as white crystals after purification. Challenges in the synthesis include achieving stereoselective oxidation to the desired sulfoxide while minimizing over-oxidation to the sulfone and controlling the formation of sulfinyl stereoisomers, which requires low-temperature conditions and careful reagent stoichiometry. Industrial-scale processes report overall yields of 70–80%, with emphasis on impurity control for residual thioether and stereoisomeric sulfinyl byproducts through chromatographic purification and crystallization. The original synthesis was patented in 1986 by Eisai Co., Ltd., with priority dating to November 13, 1986 (US Patent 5,045,552).

History

Development

Rabeprazole was invented by scientists at Co., Ltd. in and patented in 1986, with the Japanese priority application filed on November 13, 1986, under the development code E3810. The compound emerged from research aimed at advancing proton pump inhibitors (PPIs), building on earlier derivatives, and was later developed through a between Eisai and Janssen Pharmaceutica N.V. in , where it was also coded as LY307640. The original synthesis involved oxidation of a thioether precursor to form the sulfinyl group essential for its activity, as detailed in the foundational family. Preclinical development emphasized rabeprazole's design as a PPI with enhanced rapid activation to overcome the slower onset of omeprazole, enabling quicker inhibition of secretion. In , including rat and dog models of stimulated acid output, rabeprazole exhibited superior potency and duration of acid control compared to omeprazole, with more complete suppression of basal and histamine-stimulated secretion at equivalent doses. These findings highlighted its potential for faster therapeutic onset in conditions like peptic ulcers and gastroesophageal reflux. Early phase I and II clinical trials in the 1990s, involving healthy volunteers and patients with GERD or peptic ulcers, confirmed rabeprazole's efficacy in reducing acid secretion and promoting healing, with observable within the first dose. Unlike other PPIs such as omeprazole, rabeprazole showed minimal dependence on metabolism, resulting in fewer drug interactions and more consistent across populations. Milestones included key publications in 1998 elucidating its mechanism as an irreversible, noncompetitive inhibitor of the H+/K+-ATPase , supporting its differentiation from prior PPIs.

Regulatory approvals

Rabeprazole was first approved in on October 14, 1997, by the Ministry of Health, Labour and Welfare for the treatment of (GERD) and peptic ulcers, and marketed as Pariet by Co., Ltd. In , the granted marketing authorization in the third quarter of 1998 for multiple indications, including symptomatic treatment of GERD, healing and prevention of relapse of erosive or ulcerative gastro-oesophageal reflux, and healing of duodenal and benign gastric ulcers, under the brand name Pariet; it was first launched in the in September 1998. The United States Food and Drug Administration approved rabeprazole on August 19, 1999, as Aciphex delayed-release tablets (developed by Eisai in collaboration with Janssen-Ortho) for short-term treatment of erosive or ulcerative GERD, maintenance of healing of erosive esophagitis, healing of duodenal ulcers, and treatment of pathological hypersecretory conditions including Zollinger-Ellison syndrome. In India, the Central Drugs Standard Control Organization approved rabeprazole on December 27, 2001, as an antiulcer proton pump inhibitor for GERD and peptic ulcer disease, and it has since been widely genericized with multiple manufacturers producing versions for domestic and export markets. Generic rabeprazole sodium delayed-release tablets became available in the after the FDA approved the first abbreviated new drug applications on November 8, 2013, allowing market entry by several manufacturers including , , and . The FDA granted six months of pediatric exclusivity for Aciphex on December 11, 2012, extending market exclusivity to May 2014 based on studies fulfilling the agency's written request for pediatric data in children aged 1 to 11 years with GERD. As of November 2025, rabeprazole's regulatory approvals remain unchanged globally, with no new major authorizations or withdrawals; inhibitors such as rabeprazole are included on the WHO Model List of (23rd list, 2023) for the treatment of and gastro-oesophageal reflux disease via the complementary list.

Society and culture

Rabeprazole is classified as a prescription-only in the United States, requiring a doctor's prescription for dispensing, and it is not subject to any controlled substance scheduling under the DEA. In the , rabeprazole is authorized as a prescription-only (POM), available solely through prescription for conditions such as duodenal ulcers and . Similarly, across the , it holds marketing authorization as a prescription , with no over-the-counter approval for standard doses. In and various Asian countries, rabeprazole is available only by prescription. In , an over-the-counter version (Pariet S) was approved in April 2025 for short-term use. The patent for rabeprazole sodium expired on November 8, 2013, enabling the widespread availability of generic versions without ongoing patent litigation as of 2025.

Brand names

In the United States, rabeprazole is marketed under the brand name Aciphex by Woodward Pharma Services LLC, following its acquisition from Inc. in 2021. Originally developed and launched by in collaboration with Janssen, Aciphex is available as delayed-release tablets. Generic versions are widely available from manufacturers including and (formerly ), with generics dominating the U.S. market. A sprinkle , Aciphex Sprinkle, is also approved for pediatric use in children aged 1 to 11 years and is manufactured by Inc. In and , the primary brand is Pariet, developed and marketed by Co., Ltd. In much of , Janssen-Cilag handles distribution outside the and Germany. Generics are commonly available, including those produced by in the . In , notable brands include Rabicip from Ltd. and Razo from Ltd., alongside Pariet from . Other generic versions are produced by various local manufacturers. Globally, rabeprazole is available in oral forms such as delayed-release tablets and capsules, with no intravenous formulation approved. The global market for rabeprazole was valued at approximately $482 million in 2023, largely driven by generic competition.

Research

Unresolved mechanisms

Despite extensive use of rabeprazole, a (PPI), several mechanisms underlying its associated adverse effects remain unresolved, with much of the evidence derived from class-wide PPI studies rather than rabeprazole-specific investigations. The precise pathways linking long-term rabeprazole therapy to these risks are not fully elucidated, highlighting gaps in understanding that persist as of 2025. The association between rabeprazole and or fractures lacks a clear mechanistic , though hypotheses center on PPI-induced hypochlorhydria impairing calcium absorption in the intestine, leading to negative calcium balance and reduced bone mineral density. Another proposed pathway involves hypergastrinemia from sustained acid suppression, which may stimulate secretion or enhance (PTH) levels, thereby promoting osteoclastogenesis and . These mechanisms remain speculative, as direct causal links in rabeprazole users have not been confirmed through targeted mechanistic studies. Similarly, the etiology of , particularly , associated with rabeprazole is unknown, with competing hypotheses including a cell-mediated triggered by PPI exposure or secondary effects from magnesium depletion due to impaired intestinal absorption. Hypomagnesemia, a recognized PPI class effect, may exacerbate renal injury by altering , but the precise interplay in rabeprazole-induced cases requires further clarification. No rabeprazole-specific trials have delineated these processes, leaving the relative contributions unresolved. Infection risks, such as Clostridium difficile colitis and , are attributed to the reduced barrier under rabeprazole therapy, which facilitates survival and overgrowth. However, potential differences in these risks compared to other PPIs remain unresolved, as most evidence comes from pooled meta-analyses that aggregate PPI classes without isolating rabeprazole's profile. This limitation in comparative data hinders identification of rabeprazole-specific factors influencing susceptibility. Links to cancer, particularly gastric cancer, stem from a 2013 indicating an elevated risk with acid-suppressive therapies including PPIs, potentially due to hypergastrinemia promoting mucosal proliferation or altered microbial environments. Yet, no rabeprazole-specific causality has been established, and ongoing debates emphasize confounding factors such as infection status, indication bias, and incomplete adjustment for comorbidities in observational data. Recent reviews reinforce this uncertainty, noting persistent questions about direct versus indirect contributions. As of 2025, no dedicated rabeprazole-specific clinical trials have clarified these adverse effect mechanisms, with reliance on broader PPI class extrapolations underscoring the need for targeted to address these knowledge gaps.

Emerging applications

Development of an extended-release (ER) formulation of rabeprazole was pursued to provide prolonged suppression, but global efforts were discontinued in 2011 following clinical trials that demonstrated no significant superiority in healing erosive compared to . In two randomized, double-blind trials involving a total of 2130 patients with moderate-to-severe erosive (GERD), 50 mg rabeprazole ER achieved endoscopic healing rates of 80.0% and 77.5% at 8 weeks, comparable to 75.0% and 78.4% with 40 mg , despite superior 24-hour intragastric suppression with rabeprazole ER. Rabeprazole has been explored for managing acid hypersecretion in systemic , a rare disorder characterized by accumulation leading to gastrointestinal symptoms. Clinical guidelines and reviews recommend rabeprazole at 20 mg daily as symptomatic therapy to alleviate peptic symptoms, with evidence from case-based approaches and small observational series (typically n<50) indicating relief of dyspepsia and ulcer-related pain, though large-scale trials remain lacking due to the condition's rarity. Within the broader (PPI) class, rabeprazole shows potential in preventing progression of and NSAID-induced ulcers, often in combination regimens. PPIs like rabeprazole are recommended to control reflux and reduce risk in , with cohort studies suggesting up to 50% lower progression rates to high-grade or in adherent patients, though rabeprazole-specific data derive from class-wide extrapolations and small combination trials with antireflux . For NSAID-induced ulcers, a study in healthy volunteers on clopidogrel plus low-dose aspirin demonstrated that rabeprazole 10 mg daily significantly prevented gastric mucosal injury (reduced modified Lanza scores) without impairing antiplatelet effects, with efficacy varying by genotype. As of 2025, no new regulatory approvals for rabeprazole have emerged, with research shifting toward de-prescribing strategies to address long-term risks such as fractures and infections. Guidelines emphasize stepwise de-prescribing in low-risk patients after 8-12 weeks, reducing PPI exposure by 50-70% without symptom recurrence in observational cohorts, to mitigate overuse. Concurrent microbiome studies reveal that chronic rabeprazole use alters gut composition, increasing oral-derived bacteria like and decreasing diversity, potentially linked to difficile risk, though causality requires further prospective validation. Investigational applications include (EoE) and prevention of post-endoscopy bleeding. In PPI-responsive esophageal eosinophilia—a subset now integrated into EoE—a comparative study found 20 mg rabeprazole daily induced histologic remission (eosinophil count <15/hpf) in 65% of 40 patients over 8 weeks, equivalent to and . For post-endoscopic treatment of bleeding peptic ulcers, high-dose oral rabeprazole (20 mg twice daily for 72 hours) resulted in a rebleeding rate of 3.7% within 3 days in a randomized of 106 patients, comparable to intravenous omeprazole and supporting its use in outpatient settings. Recent studies have also explored rabeprazole in dual therapy regimens for H. pylori eradication, showing eradication rates comparable to vonoprazan-based dual therapies.

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