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Rabeprazole sodium (LY-307640 sodium) is a novel, potent and 2nd-generation proton pump inhibitor (PPI) that is used as an antiulcer drug. It irreversibly inactivates gastric H+/K+-ATPase and induces apoptosis. Rabeprazole acts as an uridine nucleoside ribohydrolase (UNH) inhibitor with an IC50 of 0.3 μM. Rabeprazole can be used for the research of gastric ulcerations and gastroesophageal reflux. It is a partially reversible gastric proton pump inhibitor and also an inhibitor of ATP4.
Physicochemical Properties
| Molecular Formula | C18H20N3NAO3S |
| Molecular Weight | 381.4245 |
| Exact Mass | 381.112 |
| CAS # | 117976-90-6 |
| Related CAS # | Rabeprazole;117976-89-3;Rabeprazole-d4 sodium;Rabeprazole-d4;934295-48-4;Rabeprazole Sulfide;117977-21-6;Rabeprazole-d3 sodium;1216494-11-9 |
| PubChem CID | 14720269 |
| Appearance | White to off-white solid powder |
| Density | 0.45~0.55 g/ml |
| Boiling Point | 603.9ºC at 760 mmHg |
| Melting Point | 140-141ºC dec. |
| Flash Point | 319.1ºC |
| LogP | 3.484 |
| Hydrogen Bond Donor Count | 0 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 26 |
| Complexity | 446 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | KRCQSTCYZUOBHN-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C18H20N3O3S.Na/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;/q-1;+1 |
| Chemical Name | sodium;2-[[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl]benzimidazol-1-ide |
| Synonyms | LY307640 sodium; LY-307640 sodium; LY 307640 sodium; Rabeprazole Sodium; Pariet; Aciphex; Rabeprazole sodium salt; Rebeprazole sodium;3810, E; Aciphex; dexrabeprazole; E 3810; E3810; LY 307640; LY-307640; LY307640; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
Rabeprazole Sodium is a proton pump inhibitor (PPI) that acts by inhibiting the H+/K+-ATPase (proton pump) in gastric parietal cells. [3] |
| ln Vitro |
After 0.2 mM treatment for 16 hours, rabeprazole eliminated the viability of human cells [2]. In MKN-28 cells, rabeprazole totally suppressed ERK1/2 phosphorylation. MKN-28 cell line ERK 1/2 phosphorylation was significantly suppressed when the cell line was cultured in toxin media (pH 5.4) for two hours and then attenuated with rabeprazole (0.2 mM) for two hours [2]. Treatment with rabeprazole (0.2 mM) for 16 hours led to a significant decrease in the viability of human gastric cancer cell lines (MKN-28, KATO III, MKN-45) under acidic conditions, as determined by trypan blue dye exclusion assay. The inhibitory effect was most pronounced in MKN-28 cells. [2] Exposure to 0.2 mM rabeprazole induced significant apoptosis in AGS gastric cancer cells in a time-dependent manner. After 72 hours of treatment, the apoptosis rate reached 72.21 ± 3.24% compared to 3.20 ± 0.26% in the control group, as measured by Annexin V-FITC/PI staining and flow cytometry analysis. This indicated that rabeprazole mainly induced early apoptosis. [2] Western blot analysis showed that pretreatment with 0.2 mM rabeprazole for 2 hours completely inhibited the phosphorylation of Extracellular signal-Regulated Kinase 1/2 (ERK1/2) in MKN-28 cells cultured at pH 5.4. A similar inhibitory effect on ERK1/2 phosphorylation was observed in AGS cells treated with rabeprazole across different pH levels (7.4, 6.4, 5.4). However, this effect was not observed in KATO III or MKN-45 cells under the same conditions. The study concluded that the antiproliferative effect of rabeprazole is mediated, at least in part, through the inactivation of the ERK1/2 signaling pathway. [2] Reverse Transcription-Polymerase Chain Reaction (RT-PCR) analysis revealed that the α-subunit of H+/K+-ATPase was highly expressed in KATO III and MKN-28 cells, but weakly expressed in MKN-45 cells. The β-subunit was equally expressed across these cell lines. [2] |
| ln Vivo |
In female mice, rabeprazole sodium (10 mg/kg; lateral every 48 hours for 18 weeks) significantly reduces serum calcium levels, causes a decrease in bone mineral density (BMD), and results in secondary hyperparathyroidism [3]. Long-term treatment (18 weeks) with rabeprazole (10 mg/kg every 48 h, P.O.) in female mice led to a significant reduction in femur bone mineral density (BMD) as measured by X-ray densitometry. This was associated with decreased serum calcium levels and the development of secondary hyperparathyroidism. Histopathological examination of femurs revealed widely separated, thin-walled bone trabeculae with widened inter-trabecular spaces and an increased number of osteoclasts. Immunohistochemical analysis showed increased staining for Tartrate-Resistant Acid Phosphatase (TRAP, an osteoclast activity marker) and osteopontin in the bone of rabeprazole-treated mice compared to the vehicle group. [3] Co-administration of calcium carbonate (0.5% w/w mixed with diet) or alendronate (1 mg/kg/week, i.p.) with rabeprazole for 18 weeks significantly restored the mean femur BMD, though not fully to control levels. Both interventions decreased the rabeprazole-induced elevation in TRAP and osteopontin immunostaining in bone. Histologically, both treatments resulted in thicker bone trabeculae compared to the rabeprazole-only group. Specifically, alendronate co-treatment led to the appearance of quiescent osteoclasts with inactive nuclei. [3] |
| Cell Assay |
Cell Viability Assay[2] Cell Types: Three gastric cancer cell lines KATO III, MKN-28 and MKN-45 Tested Concentrations: 0.2 mM Incubation Duration: 16 hrs (hours) Experimental Results: Treatment resulted in diminished viability of all tested cancer cell lines, comparable to KATO III Compared with MKN-28 cells, the cell viability was Dramatically diminished compared with MKN-45 cells. Western Blot Analysis[2] Cell Types: Three gastric cancer cell lines (KATO III, MKN-28 and MKN-45)[2] Tested Concentrations: 0.2 mM Incubation Duration: 2 hrs (hours) pretreatment Experimental Results: Result in strong inhibition of ERK 1/2 Phosphorylated in MKN-28 cells, but no similar effect was observed in KATO III and MKN-45 cells. Cell Viability Assay (Dye Exclusion): To assess the effect of acidity and drugs on cell viability, gastric cancer cell lines (e.g., KATO III, MKN-28, MKN-45, AGS) and a non-cancer gastric cell line (GES-1) were cultured in media adjusted to various pH levels (e.g., 7.5/7.4, 6.5/6.4, 5.5/5.4) for specified durations (16-24 hours). For drug treatment, cells were pretreated with rabeprazole (e.g., 0.1 mM, 0.2 mM) or the ERK1/2 inhibitor PD98059 for 2 hours before being cultured in media at different pH levels for an additional 16 hours. After treatment, cells were harvested and stained with trypan blue. Viable (unstained) and dead (stained) cells were counted manually using a hemocytometer. Cell viability percentage was calculated as (number of viable cells / total number of cells) × 100. [2] Apoptosis Detection by Flow Cytometry: To analyze apoptosis, AGS cells were treated with 0.2 mM rabeprazole for 24 or 72 hours. After treatment, cells were harvested, washed with cold phosphate-buffered saline (PBS), and then resuspended in binding buffer. The cell suspension was incubated with Annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI) in the dark at room temperature for 15 minutes. Subsequently, the stained cells were analyzed by flow cytometry. Cells positive for Annexin V-FITC only were considered early apoptotic, while cells positive for both Annexin V-FITC and PI were considered late apoptotic or dead. [2] Western Blot Analysis for ERK1/2 Phosphorylation: Treated and control cells were harvested, washed with cold PBS, and lysed in cold lysis buffer. After incubation on ice for 30 minutes, lysates were centrifuged at high speed (12,000 × g) for 10 minutes at 4°C to collect supernatants. Protein concentration was determined. Equal amounts of protein (50 µg) were separated by electrophoresis on 12% sodium dodecyl sulfate-polyacrylamide gels and then transferred onto polyvinylidene difluoride (PVDF) membranes. The membranes were blocked with 5% bovine serum albumin in Tris-buffered saline with Tween® 20 (TBST) for 2 hours at room temperature. They were then incubated overnight at 4°C with primary antibodies specific for phosphorylated-ERK1/2 (p-ERK1/2) and total ERK1/2. After washing, membranes were incubated with appropriate secondary antibodies, and protein bands were visualized using a chemiluminescence detection system. [2] Reverse Transcription-Polymerase Chain Reaction (RT-PCR) for H+/K+-ATPase Subunits: Total RNA was extracted from gastric cancer cell lines using a standard reagent. Two micrograms of total RNA were reverse transcribed into complementary DNA (cDNA). PCR amplification was performed using specific primers for the α-subunit and β-subunit of human H+/K+-ATPase, with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as an internal control. The PCR conditions involved an initial denaturation step, followed by 38 cycles of denaturation, annealing, and extension, with a final extension step. The amplified products were separated by electrophoresis on a 1% agarose gel and visualized under UV light after staining with ethidium bromide. [2] |
| Animal Protocol |
Animal/Disease Models: Female Swiss albino mice (body weight 18-26 g) [3] Doses: 10 mg/kg Route of Administration: Oral; every 48 hrs (hrs (hours)) for 18 weeks Experimental Results: Serum calcium levels compared with vehicle-treated group Dramatically lower (5.5±2.07 vs. 9.68±2.77). Eighty female Swiss albino mice (18-26 g) were used. They were divided into four groups (n=20 per group) and treated for 18 weeks. Group I (Vehicle) received distilled water (12 ml/kg, P.O.). Group II (Rabeprazole control) received rabeprazole (10 mg/kg, P.O., every 48 hours). Group III (Rabeprazole + Calcium) received rabeprazole (10 mg/kg, P.O., every 48 hours) along with dietary calcium carbonate (0.5% w/w mixed thoroughly with the standard chow diet). Group IV (Rabeprazole + Alendronate) received rabeprazole (10 mg/kg, P.O., every 48 hours) and alendronate (1 mg/kg, administered intraperitoneally once per week). At the end of the experiment, blood was collected via intracardiac puncture for serum analysis of calcium, phosphorus, and parathyroid hormone (PTH). Mice were then sacrificed by cervical dislocation. The right femur from each mouse was fixed and used for X-ray densitometry analysis using a digital X-ray unit and Digora software. The left femur was fixed, decalcified, embedded in paraffin, and sectioned for histopathological examination with Hematoxylin and Eosin (H&E) staining and immunohistochemical staining for osteopontin and TRAP. [3] |
| Toxicity/Toxicokinetics |
The primary toxicity/side effect investigated in this study was the induction of osteopenia (reduced bone density). Long-term rabeprazole treatment (10 mg/kg every 48 h for 18 weeks, P.O.) in female mice caused significant bone loss, hypocalcemia, and secondary hyperparathyroidism, indicating a detrimental effect on bone metabolism. [3] |
| References |
[1]. Identification of Proton-Pump Inhibitor Drugs That Inhibit Trichomonas Vaginalis Uridine Nucleoside Ribohydrolase. Bioorg Med Chem Lett. 2014 Feb 15;24(4):1080-4. [2]. Rabeprazole Exhibits Antiproliferative Effects on Human Gastric Cancer Cell Lines. Oncol Lett. 2014 Oct;8(4):1739-1744. [3]. Supplement With Calcium or Alendronate Suppresses Osteopenia Due to Long Term Rabeprazole Treatment in Female Mice: Influence on Bone TRAP and Osteopontin Levels. Front Pharmacol. 2020 May 13;11:583. |
| Additional Infomation |
Rabeprazole sodium is an organic sodium salt. It contains a rabeprazole(1-). Rabeprazole Sodium is the sodium salt of the prodrug rabeprazole, a substituted benzimidazole proton pump inhibitor, with potential anti-ulcer activity. After protonation, accumulation, and transformation to the active sulfenamide within the acidic environment of gastric parietal cells, rabeprazole selectively and irreversibly binds to and inhibits the H+, K+ATPase (hydrogen-potassium adenosine triphosphatase) enzyme system located on the parietal cell secretory surface, inhibiting gastric acid secretion. A 4-(3-methoxypropoxy)-3-methylpyridinyl derivative of timoprazole that is used in the therapy of STOMACH ULCERS and ZOLLINGER-ELLISON SYNDROME. The drug inhibits H(+)-K(+)-EXCHANGING ATPASE which is found in GASTRIC PARIETAL CELLS. See also: Rabeprazole (has active moiety). Drug Indication Treatment of duodenal ulcer, Treatment of gastric ulcer, Treatment of gastro-oesophageal reflux disease, Treatment of Helicobacter pylori in patients with peptic ulcer disease, Treatment of Zollinger-Ellison syndrome Rabeprazole is a proton pump inhibitor (PPI) widely prescribed for acid-related conditions like gastric ulcers and gastroesophageal reflux. There is growing concern about its potential side effect of increasing the risk of osteoporosis and fractures with long-term use. The proposed mechanisms include decreased calcium absorption due to hypochlorhydria (reduced stomach acid) and/or a direct inhibitory effect on osteoclastic H+/K+-ATPase. This study in female mice demonstrates that long-term rabeprazole treatment induces osteopenia and suggests that dietary calcium supplementation or co-administration of the bisphosphonate alendronate can partially mitigate these adverse effects on bone. The authors conclude that calcium or alendronate could be considered for female patients on long-term PPI therapy who are at risk of osteopenia, with calcium being a potentially safer long-term option. [3] |
Solubility Data
| Solubility (In Vitro) |
H2O : ≥ 100 mg/mL (~262.18 mM) DMSO : ≥ 48 mg/mL (~125.85 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.45 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.45 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.08 mg/mL (5.45 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6218 mL | 13.1089 mL | 26.2178 mL | |
| 5 mM | 0.5244 mL | 2.6218 mL | 5.2436 mL | |
| 10 mM | 0.2622 mL | 1.3109 mL | 2.6218 mL |