Rabeprazole

Rabeprazole, sold under the brand name Aciphex, among others, is a medication that decreases stomach acid. Effectiveness is similar to other proton pump inhibitors (PPIs). It is taken by mouth.

Rabeprazole was patented in 1986, and approved for medical use in 1997. It is available as a generic medication.

Medical uses

thumb|left|Brand-name rabeprazole tablets.

thumb|right|Bottle of rabeprazole 20 mg tablets.

Rabeprazole, like other proton pump inhibitors such as omeprazole, is used for the purposes of gastric acid suppression. This effect is beneficial for the treatment and prevention of conditions in which gastric acid directly worsens symptoms, such as duodenal and gastric ulcers. acid suppression can provide symptomatic relief. 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.

Rabeprazole is also useful alongside antibiotic therapy for the treatment of the pathogen Helicobacter pylori, which otherwise thrives in acidic environments.

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. 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. This was after the publishing of an in vivo study that detected changes in bone morphology in rats treated with esomeprazole. In these rats, the following observations were noted:

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.

Cross-reactivity

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).

Adverse effects

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). The most common side effects include headache, nausea, and diarrhea.).

Gastrin is an endogenous human hormone that stimulates gastric acid secretion and regulating the growth of certain cells in the stomach. 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.

Prolonged elevated serum gastrin has been shown to cause rat ECL cells to form carcinoid tumors. The studies included in the meta-analysis did not differentiate between rabeprazole and other PPIs, 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. A case of rabeprazole-induced iron deficiency anemia has been reported. Theoretically, rabeprazole could induce an iron deficiency anemia by reducing the dietary absorption of iron, which requires acid for bioavailability.

Osteoporosis and fractures

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). 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. Midodronic acid is a bisphosphonate class drug used to prevent fractures in osteoporosis. 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). of case-control and cohort studies. 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.

Other enteric, infectious organisms associated with PPI use include Campylobacter and Salmonella. Both pathogens are sensitive to acid; 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). In a clinical trial of 255 Japanese patients, the incidence of PPI-associated diarrhea did not differ between rabeprazole, omeprazole, or lansoprazole.

Nephrotoxicity

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). 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. 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. which resolved after discontinuation of both drugs. Notably, rabeprazole has been used in higher doses for the treatment of hypersecretory conditions like Zollinger-Ellison syndrome (up to 120 mg daily).

Interactions

Drug-drug interactions

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.

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.

! PPI

!style="width: 250px;"|Omeprazole

!style="width: 250px;"|Esomeprazole

!style="width: 250px;"|Lansoprazole

!style="width: 250px;"|Dexlansoprazole

!style="width: 250px;"|Pantoprazole

!style="width: 250px;"|Rabeprazole

! pKa

| 4.13

| 4.01

| 9.35

| 3.96

| 4.90

Pharmacokinetics

Rabeprazole's bioavailability is approximately 52%, meaning that 52% of orally administered dose is expected to enter systemic circulation (the bloodstream). 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. Rabeprazole possess properties of both acids and bases, making it an amphotere.]]

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).

{| class="wikitable"

!PPI

! style="width: 250px;" |Omeprazole

! style="width: 250px;" |Esomeprazole

! style="width: 250px;" |Lansoprazole

!Chemical structure

| style="text-align: center;" |link=https://en.wikiversity.org/wiki/File:Omeprazole.svg|200x200px

| style="text-align: center;" |link=https://en.wikiversity.org/wiki/File:Esomeprazole.svg|200x200px

| style="text-align: center;" |link=https://en.wikiversity.org/wiki/File:Lansoprazole.svg|200x200px

{| class="wikitable"

!PPI

! style="width: 250px;" |Dexlansoprazole

! style="width: 250px;" |Pantoprazole

! style="width: 250px;" |Rabeprazole

!Chemical structure

| style="text-align: center;" |link=https://en.wikiversity.org/wiki/File:Dexlansoprazole.svg|200x200px

| style="text-align: center;" |link=https://en.wikiversity.org/wiki/File:Pantoprazole.svg|220x220px

| style="text-align: center;" |link=https://en.wikiversity.org/wiki/File:Rabeprazole.png|210x210px

Physiochemical properties

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. In 1999, one year later, rabeprazole was approved for use in the United States.

Development

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.

Society and culture

Legal status

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

Brand names

Rabeprazole has been sold in a number of brand names:

{| class="wikitable mw-collapsible mw-collapsed" style="width:100%"

|+ List of trade names for rabeprazole