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Rabeprazole, sold under the brand name Aciphex, among others, is a medication that decreases
stomach acid Gastric acid or stomach acid is the acidic component – hydrochloric acid – of gastric juice, produced by parietal cells in the gastric glands of the stomach lining. In humans, the pH is between one and three, much lower than most other an ...
. It is used to treat
peptic ulcer disease Peptic ulcer disease is when the inner part of the stomach's gastric mucosa (lining of the stomach), the first part of the small intestine, or sometimes the lower esophagus, gets damaged. An ulcer in the stomach is called a gastric ulcer, while ...
,
gastroesophageal reflux disease Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is a chronic upper gastrointestinal disease in which stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/or ...
, and excess stomach acid production such as in
Zollinger–Ellison syndrome Zollinger–Ellison syndrome (Z-E syndrome) is a disease in which tumors cause the stomach to produce too much acid, resulting in peptic ulcers. Symptoms include abdominal pain and diarrhea. The syndrome is caused by the formation of a gastrinoma ...
. It may also be used in combination with other medications to treat ''
Helicobacter pylori ''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, Flagellum#bacterial, flagellated, Bacterial cellular morphologies#Helical, helical bacterium. Mutants can have a rod or curved rod shape that exhibits l ...
''. Effectiveness is similar to other
proton pump inhibitors Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of gastric acid, stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase, H+/K+ ATPase proton pump. The body ...
(PPIs). It is taken by mouth. Common side effects include
constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...
, feeling weak, and throat inflammation. Serious side effects may include
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...
, low blood magnesium, ''Clostridioides difficile'' infection, and
pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...
. Use in
pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...
and
breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...
is of unclear safety. It works by blocking H+/K+-ATPase in the
parietal cell Parietal cells (also known as oxyntic cells) are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor. These cells are located in the gastric glands found in the lining of the fundus and body regions o ...
s of the stomach. Rabeprazole was patented in 1986, and approved for medical use in 1997. It is available as a
generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
. In 2017, it was the 288th most commonly prescribed medication in the United States, with more than 1million prescriptions.


Medical uses

Rabeprazole, like other
proton pump inhibitors Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of gastric acid, stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase, H+/K+ ATPase proton pump. The body ...
such as
omeprazole Omeprazole, sold under the brand names Prilosec and Losec, among others, is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent up ...
, 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. In the setting of
gastroesophageal reflux disease Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is a chronic upper gastrointestinal disease in which stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/or ...
(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), acid suppression can provide symptomatic relief. 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 Multiple endocrine neoplasia type 1 (MEN-1 aka Wermer Syndrome) is one of a group of disorders, the multiple endocrine neoplasias, that affect the endocrine system through development of neoplastic lesions in pituitary, parathyroid gland and pa ...
(MEN-1), and systemic
mastocytosis Mastocytosis, a type of mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from ...
. In an
open-label An open-label trial, or open trial, is a type of clinical trial in which information is not withheld from trial participants. In particular, both the researchers and participants know which treatment is being administered. This contrasts with a do ...
, 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. Only one patient withdrew from the study due to an elevation in
creatine phosphokinase Creatine kinase (CK), also known as creatine phosphokinase (CPK) or phosphocreatine kinase, is an enzyme () expressed by various tissues and cell types. CK catalyses the conversion of creatine and uses adenosine triphosphate (ATP) to create phos ...
judged to be possibly due to rabeprazole, while rabeprazole was otherwise well-tolerated in this population. 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 H2 antagonists, sometimes referred to as H2RAs and also called H2 blockers, are a class of pharmaceutical drug, medications that block the action of histamine at the histamine H2 receptor, histamine H2 receptors of the parietal cells in the stoma ...
are routinely used to counter the histamine-mediated acid secretion found in this disorder. Rabeprazole is also useful alongside
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...
therapy for the treatment of the pathogen ''
Helicobacter pylori ''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, Flagellum#bacterial, flagellated, Bacterial cellular morphologies#Helical, helical bacterium. Mutants can have a rod or curved rod shape that exhibits l ...
'', which otherwise thrives in acidic environments. 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. Notably, ''H. pylori'' eradication with antibiotics and rabeprazole was also shown to prevent development of second
gastric cancer Stomach cancer, also known as gastric cancer, is a malignant tumor of the stomach. It is a cancer that develops in the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes ...
in a
randomized trial In science, randomized experiments are the experiments that allow the greatest reliability and validity of statistical estimates of treatment effects. Randomization-based inference is especially important in experimental design and in survey sampl ...
in high-risk South Korean patients with early stomach cancer treated by
endoscopy An endoscopy is a procedure used in medicine to look inside the body. The endoscopy procedure uses an endoscope to examine the interior of a hollow organ or cavity of the body. Unlike many other medical imaging techniques, endoscopes are insert ...
. Thus, rabeprazole is US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) approved for the treatment of symptomatic
GERD Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is a chronic upper gastrointestinal disease in which stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/or ...
in adolescents and adults, healing duodenal ulcers in adults, eradication of ''Helicobacter pylori'', and pathologic hypersecretory conditions.


Available forms

Rabeprazole is available in 10 and 20 mg, delayed-release tablets (pictured below). Rabeprazole-based products, like other
proton pump inhibitor Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. The body eventually synthesizes ne ...
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.


Specific populations


Pediatrics

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


Pregnancy

The FDA originally labeled rabeprazole as a
pregnancy category The pregnancy category of a medication is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does ''not'' include any risks conferred by pharmaceutical agents or their ...
B drug (meaning that
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...
research failed to demonstrate a fetal hazard, though human studies are lacking), 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 Morphology, from the Greek and meaning "study of shape", may refer to: Disciplines *Morphology (archaeology), study of the shapes or forms of artifacts *Morphology (astronomy), study of the shape of astronomical objects such as nebulae, galaxies, ...
in rats treated with
esomeprazole Esomeprazole, sold under the brand name Nexium r Neksiumamong others, is a medication which reduces stomach acid. It is used to treat gastroesophageal reflux disease, peptic ulcer disease, and Zollinger–Ellison syndrome. Its effectiveness ...
. In these rats, the following observations were noted: * shortened femurs, decreased width and thickness of
cortical bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, an ...
, decreased thickness of the tibial growth plate, and minimal to mild
bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
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.


Lactation

It is expected that rabeprazole will be secreted into human
breast milk Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by the mammary glands in the breasts of women. Breast milk is the primary source of nutrition for newborn infants, comprising fats, proteins, carbohydrates, and a var ...
, though the clinical impact of this is still unknown. Avoiding rabeprazole during
breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...
confers to lowest possible risk.


Geriatrics

Advanced age does not appear to clinically impact rabeprazole's metabolism. However, elevations in the maximum plasma concentration and the total drug exposure (
area under the curve In mathematics, an integral is the continuous analog of a sum, which is used to calculate areas, volumes, and their generalizations. Integration, the process of computing an integral, is one of the two fundamental operations of calculus,Inte ...
, AUC) have occurred.


Japanese ancestry

In a study on rabeprazole's
pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...
, the AUC was elevated by approximately 50–60% in men of
Japanese Japanese may refer to: * Something from or related to Japan, an island country in East Asia * Japanese language, spoken mainly in Japan * Japanese people, the ethnic group that identifies with Japan through ancestry or culture ** Japanese diaspor ...
ancestry compared to men in the United States. See the pharmacogenetics section below for a pharmacogenetic explanation of these findings.


Kidney or liver problems

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 Dialysis may refer to: * Dialysis (chemistry), a process of separating molecules in solution **Electrodialysis, used to transport salt ions from one solution to another through an ion-exchange membrane under the influence of an applied electric po ...
for kidney problems. Severe liver problems like
cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...
of the liver do affect rabeprazole's elimination half-life, but not to a degree of dangerous accumulation. In a review of patients taking rabeprazole while having
end-stage kidney disease Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three m ...
and mild-to-moderate severity, chronic compensated cirrhosis of the liver, the alteration in rabeprazole's metabolism was not clinically meaningful.


Contraindications

Rabeprazole is contraindicated in the following populations and situations: * people with a known hypersensitivity to rabeprazole, substituted
benzimidazoles Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound may be viewed as fused rings of the aromatic compounds benzene and imidazole. It is a white solid that appears in form of tabular crystals. Preparation Be ...
(which are chemically similar to rabeprazole, like
omeprazole Omeprazole, sold under the brand names Prilosec and Losec, among others, is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent up ...
), or any other component of the capsule formulation (e.g. certain dyes) * concurrent use of
rilpivirine Rilpivirine, sold under the brand name Edurant among others, is a medication, developed by Tibotec, used for the treatment of HIV/AIDS. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency (pharma ...
, a medication used to treat
HIV The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the im ...
infection


Hypersensitivity


Syndrome

An allergy to a
PPI PPI may refer to: Science and technology Biochemistry * PPi, the anion P2O74−, a pyrophosphate * Polyproline I helix * Protein–protein interaction Medicine * Patient and public involvement * Prepulse inhibition, of a later pulse * Proton-pump ...
like rabeprazole may take the form of
type I hypersensitivity Type I hypersensitivity (or immediate hypersensitivity), in the Hypersensitivity, Gell and Coombs classification of allergic reactions, is an allergic reaction provoked by re-exposure to a specific type of antigen referred to as an allergen. Type ...
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 Anaphylaxis (Greek: 'up' + 'guarding') is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the use of emergency medication on site. It typicall ...
has been reported, as well as several whole group hypersentivities.


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 Omeprazole, sold under the brand names Prilosec and Losec, among others, is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent up ...
,
esomeprazole Esomeprazole, sold under the brand name Nexium r Neksiumamong others, is a medication which reduces stomach acid. It is used to treat gastroesophageal reflux disease, peptic ulcer disease, and Zollinger–Ellison syndrome. Its effectiveness ...
, and
pantoprazole Pantoprazole, sold under the brand name Protonix, among others, is a medication used for the treatment of stomach ulcers, short-term treatment of erosive esophagitis due to gastroesophageal reflux disease (GERD), maintenance of healing of ero ...
, but not to
lansoprazole Lansoprazole, sold under the brand name Prevacid among others, is a medication which reduces stomach acid. It is a proton pump inhibitor (PPI), used to treat peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndr ...
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 Omeprazole, sold under the brand names Prilosec and Losec, among others, is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent up ...
,
esomeprazole Esomeprazole, sold under the brand name Nexium r Neksiumamong others, is a medication which reduces stomach acid. It is used to treat gastroesophageal reflux disease, peptic ulcer disease, and Zollinger–Ellison syndrome. Its effectiveness ...
,
pantoprazole Pantoprazole, sold under the brand name Protonix, among others, is a medication used for the treatment of stomach ulcers, short-term treatment of erosive esophagitis due to gastroesophageal reflux disease (GERD), maintenance of healing of ero ...
, and
lansoprazole Lansoprazole, sold under the brand name Prevacid among others, is a medication which reduces stomach acid. It is a proton pump inhibitor (PPI), used to treat peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndr ...
).


Rilpivirine

Rilpivirine Rilpivirine, sold under the brand name Edurant among others, is a medication, developed by Tibotec, used for the treatment of HIV/AIDS. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency (pharma ...
, a
non-nucleoside reverse transcriptase inhibitor Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replicatio ...
(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.


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 Pharmacovigilance (PV, or PhV), also known as drug safety, is the pharmaceutical science relating to the "collection, detection, assessment, monitoring, and prevention" of adverse effects with pharmaceutical products. The etymological roots ...
clinical trial). The
side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...
profile is similar to that of
omeprazole Omeprazole, sold under the brand names Prilosec and Losec, among others, is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent up ...
. The
side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...
profile is similar to that of
omeprazole Omeprazole, sold under the brand names Prilosec and Losec, among others, is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent up ...
and other commonly used PPIs. The most common side effects include
headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
, and
diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
. Rare side effects include rashes, flu-like symptoms, and infections (including by the gastrointestinal pathogen ''
Clostridioides difficile ''Clostridioides difficile'' ( syn. ''Clostridium difficile'') is a bacterium known for causing serious diarrheal infections, and may also cause colon cancer. It is known also as ''C. difficile'', or ''C. diff'' (), and is a Gram-positive spec ...
''). Rare instances of rabeprazole-induced
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
injury (also known as hepatotoxicity) have been reported. Characteristic proton-pump inhibitor hepatotoxicity occurs within the first 4 weeks of starting the medication.
Gastrin Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas. ...
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 Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Discovered in 19 ...
in the stomach, respond to prolonged gastrin exposure by growing and proliferating. Rabeprazole is associated with elevated serum gastrin levels (hypergastrinemia), which occurs through inhibiting the negative feedback of stomach acid on gastrin secretion by
G cell A G cell or gastrin cell is a type of cell in the stomach and duodenum that secretes gastrin. It works in conjunction with gastric chief cells and parietal cells. G cells are found deep within the pyloric glands of the stomach antrum, and occasi ...
s in the antrum of the stomach. The elevation in serum gastrin levels are thought to be dependent upon the degree of rabeprazole's
CYP2C19 Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some ...
metabolism. Rabeprazole is not as significantly metabolized by CYP2C19 compared to other medications in the same class, like omeprazole. 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. Prolonged elevated serum gastrin has been shown to cause rat ECL cells to form
carcinoid tumors A carcinoid (also carcinoid tumor) is a slow-growing type of neuroendocrine tumor originating in the cells of the neuroendocrine system. In some cases, metastasis may occur. Carcinoid tumors of the midgut (jejunum, ileum, appendix, and cecum) a ...
. 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. 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 Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. One of eight B vitamins, it serves as a vital cofactor (biochemistry), cofactor in DNA synthesis and both fatty acid metabolism, fatty acid and amino a ...
and
magnesium Magnesium is a chemical element; it has Symbol (chemistry), symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 ...
, leading to deficiency. A case of rabeprazole-induced
iron deficiency anemia Iron-deficiency anemia is anemia caused by a lack of iron. Anemia is defined as a decrease in the number of red blood cells or the amount of hemoglobin in the blood. When onset is slow, symptoms are often vague such as feeling tired, weak, sh ...
has been reported. Theoretically, rabeprazole could induce an iron deficiency anemia by reducing the dietary absorption of iron, which requires acid for bioavailability. Very serious side effects have been reported in people taking rabeprazole, but there is no direct evidence that rabeprazole definitely caused these side effects. These include Stevens-Johnson syndrome (a serious disease characterized by skin rash and risk of organ failure), serious
blood cell A blood cell (also called a hematopoietic cell, hemocyte, or hematocyte) is a cell produced through hematopoiesis and found mainly in the blood. Major types of blood cells include red blood cells (erythrocytes), white blood cells (leukocytes), ...
abnormalities, coma, and death. Other possible side effects, common to other PPI medications in the same class, include bone fractures due to
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...
, serious infections (including ''Clostridioides difficile''), and kidney damage (nephrotoxicity). A rare, though less understood, side effect of the PPI class is the risk of
myopathy In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meaning implies that the primary defec ...
and
rhabdomyolysis Rhabdomyolysis (shortened as rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some o ...
, a syndrome of striated muscle destruction.


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 Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to opti ...
akin to the effect of
minodronic acid Minodronic acid is a third-generation bisphosphonate drug. It is approved for use in Japan for the treatment of osteoporosis. Its mechanism of action involves inhibition Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a subs ...
in a study of gastrectomized rats. Midodronic acid is a
bisphosphonate Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed to treat osteoporosis. Evidence shows that they reduce the risk of fracture in ...
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
osteoclast An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and bone remodeling, remodeling of bones of the vertebrate, vertebral skeleton. The osteoclast disassembles and digests th ...
s (like a bisphosphonate).


Infection risk

PPIs have been associated with an increased risk for
pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...
by
meta-analyses Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...
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 475px, Map of the year each country achieved List of sovereign states by date of formation, independence. Colonization (British English: colonisation) is a process of establishing occupation of or control over foreign territories or peoples f ...
and subsequent pneumonia. 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
neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...
s and
natural killer cell Natural killer cells, also known as NK cells, are a type of cytotoxic lymphocyte critical to the innate immune system. They are a kind of large granular lymphocytes (LGL), and belong to the rapidly expanding family of known innate lymphoid cells ...
s. In line with the stomach acid suppression hypothesis for bacterial overgrowth, PPIs have also been associated with ''Clostridioides difficile'' infections. 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. Rabeprazole was identified as the causative agent in a case report of
collagenous colitis Collagenous colitis is an inflammatory condition of the colon. Together with the related condition lymphocytic colitis, it is a subtype of microscopic colitis, which is characterized by inflammation that specifically affects the colon (i.e. col ...
, inducing chronic, watery diarrhea. Other enteric, infectious organisms associated with PPI use include ''
Campylobacter ''Campylobacter'' is a type of bacteria that can cause a diarrheal disease in people. Its name means "curved bacteria", as the germ typically appears in a comma or "s" shape. According to its scientific classification, it is a genus of gram-negat ...
'' and ''
Salmonella ''Salmonella'' is a genus of bacillus (shape), rod-shaped, (bacillus) Gram-negative bacteria of the family Enterobacteriaceae. The two known species of ''Salmonella'' are ''Salmonella enterica'' and ''Salmonella bongori''. ''S. enterica'' ...
''. Both pathogens are sensitive to acid; theoretically, as above, acid suppression by PPIs should increase their
pathogen In biology, a pathogen (, "suffering", "passion" and , "producer of"), in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a Germ theory of d ...
icity. 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 Interstitial nephritis, also known as tubulointerstitial nephritis, is inflammation of the area of the kidney known as the renal interstitium, which consists of a collection of cells, extracellular matrix, and fluid surrounding the renal tubules ...
(AIN) (insufficient quality evidence),
acute kidney injury Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in renal function, kidney function that develops within seven days, as shown by an increase in serum creatinine or a decrease in urine output, or both. ...
(AKI) (low grade evidence),
chronic kidney disease Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...
(CKD) (low grade evidence), and
end-stage renal disease Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...
(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 Hypersensitivity (also called hypersensitivity reaction or intolerance) is an abnormal physiological condition in which there is an undesirable and adverse immune response to an antigen. It is an abnormality in the immune system that causes Imm ...
reaction. It has also been posited that incomplete resolution of PPI-induced acute interstitial nephritis could precede acute kidney injury and chronic kidney disease.


Muscle-related adverse events

Cases of progressive muscle weakness, muscle pain, and rhabdomyolysis following administration of PPIs have been reported in the scientific literature. However, the mechanism for these muscle-related adverse events has yet to be established. In one case, rhabdomyolysis developed in a 50 year-old patient 2 weeks after starting both rabeprazole and
domperidone Domperidone, sold under the brand name Motilium among others, is a dopamine antagonist medication which is used to treat nausea and vomiting and certain gastrointestinal problems like gastroparesis (delayed gastric emptying). It raises the ...
, a prokinetic and antiemetic agent, which resolved after discontinuation of both drugs. 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.


Overdose

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


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 Theophylline, also known as 1,3-dimethylxanthine, is a drug that inhibits phosphodiesterase and blocks adenosine receptors. It is used to treat chronic obstructive pulmonary disease (COPD) and asthma. Its pharmacology is similar to other met ...
,
warfarin Warfarin, sold under the brand name Coumadin among others. It is used as an anticoagulant, anticoagulant medication. It is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who ha ...
,
diazepam Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety disorder, anxiety, seizures, alcohol withdrawal syndr ...
, and
phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anticonvulsant, anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence se ...
. However, the acid-suppression effects of rabeprazole, like other PPIs, may interfere with the absorption of drugs that require acid, such as
ketoconazole Ketoconazole, sold under the brand name Nizoral, among others, is an antiandrogen, antifungal drug, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin inf ...
and
digoxin Digoxin (better known as digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart disease, heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. ...
. There is some evidence that
omeprazole Omeprazole, sold under the brand names Prilosec and Losec, among others, is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent up ...
and
esomeprazole Esomeprazole, sold under the brand name Nexium r Neksiumamong others, is a medication which reduces stomach acid. It is used to treat gastroesophageal reflux disease, peptic ulcer disease, and Zollinger–Ellison syndrome. Its effectiveness ...
, two medications in the same class as rabeprazole, can disturb the conversion of an
anticoagulant An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which ...
medication called
clopidogrel Clopidogrel, sold under the brand name Plavix among others, is an antiplatelet drug, antiplatelet medication used to reduce the risk of Cardiovascular disease, heart disease and stroke in those at high risk. It is also used together with aspi ...
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. Clinically serious drug-drug interactions may involve the acid-suppression effects of rabeprazole. For example, rabeprazole should not be used concomitantly with
rilpivirine Rilpivirine, sold under the brand name Edurant among others, is a medication, developed by Tibotec, used for the treatment of HIV/AIDS. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency (pharma ...
, an anti-
HIV The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the im ...
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 Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given ...
, digoxin,
iron Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...
,
mycophenolate Mycophenolic acid is an immunosuppressant medication used to prevent rejection following organ transplantation and to treat autoimmune conditions such as Crohn's disease and lupus. Specifically it is used following kidney, heart, and liver t ...
, and
tyrosine kinase inhibitors A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosph ...
like
erlotinib Erlotinib, sold under the brand name Tarceva among others, is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) ...
,
dasatinib Dasatinib, sold under the brand name Sprycel among others, is a targeted therapy medication used to treat certain cases of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Specifically it is used to treat cases that a ...
, and
nilotinib Nilotinib, sold under the brand name Tasigna among others, is an anti-cancer medication used to treat chronic myelogenous leukemia (CML) which has the Philadelphia chromosome. It may be used both in initial cases of chronic phase CML as well a ...
. There is no clinically relevant drug interaction between rabeprazole and antacids.


Food-drug interactions

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


Pharmacology


Mechanism of action

Once rabeprazole is taken by mouth, the enteric coating of the tablet allows the drug to pass through the stomach intact. Like other PPIs, rabeprazole is absorbed into the blood stream at the site of the proximal small bowel. Rabeprazole's mechanism of action involves crossing from the blood stream into the
parietal cells Parietal cells (also known as oxyntic cells) are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor. These cells are located in the gastric glands found in the lining of the fundus and body regions o ...
of the
stomach The stomach is a muscular, hollow organ in the upper gastrointestinal tract of Human, humans and many other animals, including several invertebrates. The Ancient Greek name for the stomach is ''gaster'' which is used as ''gastric'' in medical t ...
, which are the cells that are responsible for secreting
hydrochloric acid Hydrochloric acid, also known as muriatic acid or spirits of salt, is an aqueous solution of hydrogen chloride (HCl). It is a colorless solution with a distinctive pungency, pungent smell. It is classified as a acid strength, strong acid. It is ...
(HCl). At this point, rabeprazole is inactive. However, rabeprazole is then secreted into the secretory canaliculus of the parietal cells, which is the space from which acid secretion occurs. Here, acid secretion is mediated by the energy-dependent acid pumps, called hydrogen potassium adenosine triphosphatase (H+/K+ ATPase) pumps. These
enzymatic An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as produc ...
pumps have
cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
residues. After being activated by gastric (stomach) acid to a reactive
sulfenamide In organosulfur chemistry, sulfenamides (also spelled sulphenamides) are a class of organosulfur compounds characterized by the general formula , where the R groups are hydrogen, alkyl, or aryl.Capozzi, G., Modena, G., Pasquato, L. in "Chemi ...
intermediate, rabeprazole permanently binds the cysteine residues, forming
covalent A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atom ...
,
disulfide bonds In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In in ...
. 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+). 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. Rabeprazole, like other medications in the same class, cannot inhibit the H+/K+ ATPase pumps found in
lysosomes A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...
, 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. A unique feature of rabeprazole's mechanism of action in inhibiting acid secretion involves its activation. The
pKa In chemistry, an acid dissociation constant (also known as acidity constant, or acid-ionization constant; denoted ) is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction :H ...
(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. 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.


Pharmacokinetics

Rabeprazole's bioavailability is approximately 52%, meaning that 52% of orally administered dose is expected to enter systemic circulation (the bloodstream). Once in the blood, rabeprazole is approximately 96.3%-97% bound to plasma proteins. The biological
half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...
of rabeprazole in humans is approximately one hour. 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. Rabeprazole is extensively metabolized by the
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
. 90% of the drug is rendered into metabolites by the liver, which are then excreted by the
kidneys In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and right in the retro ...
. 10% of the dose is excreted in the feces. The drug metabolizing enzymes primarily responsible for rabeprazole's metabolism are
CYP2C19 Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some ...
and
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
. However, rabeprazole is mainly metabolized through non-enzymatic reduction to a thioether metabolite. Some of rabeprazole's metabolites include the following: a
thioether In organic chemistry, a sulfide (British English sulphide) or thioether is an organosulfur functional group with the connectivity as shown on right. Like many other sulfur-containing compounds, Volatile organic compound, volatile sulfides have ...
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...
metabolite, a thioether
glucuronide A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides. Glucuronidation, the conversion of chemical compounds to glucu ...
metabolite, and a
sulfone In organic chemistry, a sulfone is a organosulfur compound containing a sulfonyl () functional group attached to two carbon atoms. The central hexavalent sulfur atom is double-bonded to each of two oxygen atoms and has a single bond to each of ...
metabolite. The most common metabolites excreted in the urine are the mercapturic acid conjugate and carboxylic acid. A diagram of rabeprazole's
phase I metabolism Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set of ...
is shown below.


Pharmacogenetics

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 Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some ...
. 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 In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
is found in roughly 3–5% of
Caucasian Caucasian may refer to: Common meanings *Anything from the Caucasus region or related to it ** Ethnic groups in the Caucasus ** ''Caucasian Exarchate'' (1917–1920), an ecclesiastical exarchate of the Russian Orthodox Church in the Caucasus re ...
people, and in 17–20% of people of Asian ancestry. 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. However, rabeprazole's metabolism is primarily non-enzymatic (it is often inactivated chemically, without the participation of the body's natural drug metabolizing
enzymes An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as pro ...
). Therefore, while a person's CYP2C19 phenotype will affect rabeprazole's metabolism, it is not expected to dramatically affect the efficacy of the medication.


Chemistry

Rabeprazole is classified as a substituted
benzimidazole Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound may be viewed as fused rings of the aromatic compounds benzene and imidazole. It is a white solid that appears in form of tabular crystals. Preparation Benzimi ...
, like
omeprazole Omeprazole, sold under the brand names Prilosec and Losec, among others, is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent up ...
,
lansoprazole Lansoprazole, sold under the brand name Prevacid among others, is a medication which reduces stomach acid. It is a proton pump inhibitor (PPI), used to treat peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndr ...
, and
pantoprazole Pantoprazole, sold under the brand name Protonix, among others, is a medication used for the treatment of stomach ulcers, short-term treatment of erosive esophagitis due to gastroesophageal reflux disease (GERD), maintenance of healing of ero ...
. Rabeprazole possess properties of both acids and bases, making it an amphotere. The
acid dissociation constant In chemistry, an acid dissociation constant (also known as acidity constant, or acid-ionization constant; denoted ) is a quantitative property, quantitative measure of the acid strength, strength of an acid in Solution (chemistry), solution. I ...
(pKa) of the
pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom . It is a highly flammable, weak ...
nitrogen Nitrogen is a chemical element; it has Symbol (chemistry), symbol N and atomic number 7. Nitrogen is a Nonmetal (chemistry), nonmetal and the lightest member of pnictogen, group 15 of the periodic table, often called the Pnictogen, pnictogens. ...
is about equal to 4.


Synthesis

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 Acetic anhydride, or ethanoic anhydride, is the chemical compound with the chemical formula, formula . Commonly abbreviated , it is one the simplest organic acid anhydride, anhydrides of a carboxylic acid and is widely used in the production of c ...
results in the Polonovski reaction. Saponification followed by treatment with
thionyl chloride Thionyl chloride is an inorganic compound with the chemical formula . It is a moderately Volatility (chemistry), volatile, colourless liquid with an unpleasant acrid odour. Thionyl chloride is primarily used as a Halogenation, chlorinating reagen ...
then chlorinates the primary alcohol (5). Reaction with benzimidazole-2-thiol (6) followed by oxidation of the resulting thioether to the
sulfoxide In organic chemistry, a sulfoxide, also called a sulphoxide, is an organosulfur compound containing a sulfinyl () functional group attached to two carbon atoms. It is a polar functional group. Sulfoxides are oxidized derivatives of sulfides. E ...
yields the final product: rabeprazole (8).


Comparative chemistry

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 Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound may be viewed as fused rings of the aromatic compounds benzene and imidazole. It is a white solid that appears in form of tabular crystals. Preparation Benzimi ...
or
pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom . It is a highly flammable, weak ...
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. Esomeprazole and deslansoprazole represent
stereoisomers In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms i ...
of omeprazole and lansoprazole respectively.


Physiochemical properties

Rabeprazole is characterized as a white to yellowish-white solid in its pure form. It is soluble in a number of
solvents A solvent (from the Latin '' solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water is a solvent for p ...
. Rabeprazole is very soluble in water and
methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical compound and the simplest aliphatic Alcohol (chemistry), alcohol, with the chemical formula (a methyl group linked to a hydroxyl group, often ab ...
, freely soluble in
ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...
,
chloroform Chloroform, or trichloromethane (often abbreviated as TCM), is an organochloride with the formula and a common solvent. It is a volatile, colorless, sweet-smelling, dense liquid produced on a large scale as a precursor to refrigerants and po ...
, and
ethyl acetate Ethyl acetate commonly abbreviated EtOAc, ETAC or EA) is the organic compound with the formula , simplified to . This flammable, colorless liquid has a characteristic sweet smell (similar to pear drops) and is used in glues, nail polish removers, ...
, and is insoluble in
ether In organic chemistry, ethers are a class of compounds that contain an ether group, a single oxygen atom bonded to two separate carbon atoms, each part of an organyl group (e.g., alkyl or aryl). They have the general formula , where R and R� ...
and
n-hexane Hexane () or ''n''-hexane is an organic compound, a straight-chain alkane with six carbon atoms and the molecular formula C6H14. Hexane is a colorless liquid, odorless when pure, and with a boiling point of approximately . It is widely used as ...
. It is unstable under humid conditions.


History

Rabeprazole was first marketed in Europe in 1998. In 1999, one year later, rabeprazole was approved for use in the
United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...
.


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 The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial ...
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 Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is a chronic upper gastrointestinal disease in which stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/or ...
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 India, officially the Republic of India, is a country in South Asia. It is the List of countries and dependencies by area, seventh-largest country by area; the List of countries by population (United Nations), most populous country since ...
in December 2001. It was approved in
Japan Japan is an island country in East Asia. Located in the Pacific Ocean off the northeast coast of the Asia, Asian mainland, it is bordered on the west by the Sea of Japan and extends from the Sea of Okhotsk in the north to the East China Sea ...
in 1997, and in all European Union member countries since.


Brand names

Rabeprazole has been sold in a number of brand names:


Research

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 Esomeprazole, sold under the brand name Nexium r Neksiumamong others, is a medication which reduces stomach acid. It is used to treat gastroesophageal reflux disease, peptic ulcer disease, and Zollinger–Ellison syndrome. Its effectiveness ...
(another common PPI) for healing grade C or D
erosive esophagitis Esophagitis, also spelled oesophagitis, is a disease characterized by inflammation of the esophagus. The esophagus is a tube composed of a mucosal lining, and longitudinal and circular smooth muscle fibers. It connects the pharynx to the stomach; ...
, the development of rabeprazole-ER ceased.


References


External links

* {{Use dmy dates, date=January 2020 Benzimidazoles Ethers Drugs developed by Johnson & Johnson Janssen Pharmaceutica Japanese inventions Phenol ethers Prodrugs Proton-pump inhibitors Pyridines Sulfoxides Wikipedia medicine articles ready to translate