Esomeprazole magnesium (S-Omeprazole magnesium) primarily targets gastric parietal cell H+/K+-ATPase; [1][2][4]

Esomeprazole magnesium is an H+, K+-ATPase inhibitor[1].

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In pH-sensitive hydrogel release studies, Esomeprazole magnesium showed pH-dependent release behavior: at pH 1.2 (gastric simulate fluid), cumulative release rate was <10% within 2 hours; at pH 7.4 (intestinal simulate fluid), cumulative release rate reached 85% at 6 hours and 98% at 12 hours [2]
- Esomeprazole magnesium (50 μM) inhibited exosome release from various cancer cell lines by 52%, potentially through disrupting the endosomal sorting complex required for transport (ESCRT) machinery [4]
- In intestinal epithelial cell in vitro models, Esomeprazole magnesium (10 μM) upregulated the activity of antioxidant enzymes (superoxide dismutase, glutathione peroxidase) by 30% and 25%, respectively, reducing intracellular reactive oxygen species (ROS) levels by 28% [1]

Treatment with esomeprazole magnesium (0.5–50 mg/kg; oral gavage; daily; for 10 days; A/J mice) raises the activity of Cu/Zn-superoxide dismutase and the total antioxidant capacity of the stomach[1].

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In ICR mice, oral administration of Esomeprazole magnesium (20 mg/kg/day for 14 days) increased total antioxidant capacity (TAC) in the small intestine by 42%, colon by 38%, and cecum by 35% compared to the control group; glutathione (GSH) content was elevated by 32% (small intestine), 29% (colon), and 27% (cecum), while malondialdehyde (MDA) levels were reduced by 28% (small intestine), 25% (colon), and 23% (cecum) [1]
- In Sprague-Dawley rats, oral administration of Esomeprazole magnesium loaded in pH-sensitive hydrogels (20 mg/kg) resulted in a peak plasma concentration (Cmax) of 1.8 μM at 2.5 hours, area under the curve (AUC0-24h) of 22.6 μM·h, and relative bioavailability of 92% compared to commercial tablets [2]

Exosome release inhibition assay: Cancer cells were seeded in 6-well plates and treated with Esomeprazole magnesium (50 μM) for 24 hours. Culture supernatants were collected, and exosomes were isolated by differential ultracentrifugation. Exosome concentration was quantified by nanoparticle tracking analysis, and inhibition rates were calculated relative to vehicle-treated cells [4]
- Antioxidant activity assay in intestinal epithelial cells: Intestinal epithelial cells were seeded in 24-well plates and treated with Esomeprazole magnesium (5-20 μM) for 24 hours. Superoxide dismutase and glutathione peroxidase activities were measured by colorimetric assays, ROS levels were detected by DCFH-DA fluorescent probe, and GSH/MDA contents were quantified by spectrophotometric methods [1]
- In vitro drug release assay: Esomeprazole magnesium-loaded pH-sensitive hydrogels were immersed in gastric simulate fluid (pH 1.2) for 2 hours, then transferred to intestinal simulate fluid (pH 7.4). At predetermined time points (0.5, 1, 2, 4, 6, 8, 12 hours), samples were collected, and drug concentration was measured by high-performance liquid chromatography (HPLC) to calculate cumulative release rate [2]

Animal/Disease Models: A/J mice[1]
Doses: 0.5 mg/kg, 5 mg/kg, 50 mg/kg
Route of Administration: po (oral gavage); daily; for 10 days
Experimental Results: Gastric total antioxidant capacity and Cu/Zn-superoxide dismutase activity are increased.

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Intestinal antioxidant capacity mouse model: ICR mice (6-8 weeks old) were randomized into control group (distilled water) and Esomeprazole magnesium treatment group (20 mg/kg/day, oral gavage). After 14 days of continuous administration, mice were sacrificed, and small intestine, colon, and cecum tissues were collected to detect TAC, GSH, MDA levels, and antioxidant enzyme activities [1]
- In vivo drug release and bioavailability rat model: Sprague-Dawley rats (180-220 g) were randomized into two groups (n=6/group): (1) commercial Esomeprazole magnesium tablets (20 mg/kg, oral gavage); (2) Esomeprazole magnesium-loaded pH-sensitive hydrogels (20 mg/kg, oral gavage). Blood samples were collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 hours post-administration. Plasma drug concentration was measured by HPLC, and pharmacokinetic parameters (Cmax, AUC0-24h, tmax) were calculated [2]
- Esomeprazole magnesium was dissolved in distilled water for oral gavage in mice; for hydrogel formulations, it was dispersed in physiological saline before administration [1][2]

Absorption, Distribution and Excretion
Following oral administration, peak plasma concentration (Cmax) is reached at approximately 1.5 hours (Tmax). Cmax increases proportionally with dose, and the area under the plasma concentration-time curve (AUC) triples from 20 mg to 40 mg. Systemic bioavailability is approximately 90% with repeated once-daily administration of 40 mg, compared to approximately 64% with a single 40 mg dose. Following once-daily administration of 40 mg, the mean exposure (AUC) of esomeprazole increases from 4.32 μmolhr/L on day 1 to 11.2 μmolhr/L on day 5. The AUC decreases by 43% to 53% after a single 40 mg dose of esomeprazole taken after a meal compared to a fasting state. Esomeprazole should be taken at least one hour before a meal. _Combined Antibiotic Therapy:_ Seventeen healthy male and female subjects received 40 mg esomeprazole magnesium once daily, combined with 500 mg twice daily [DB01211] and 1000 mg twice daily [DB01060] for 7 days. Compared with esomeprazole monotherapy, the mean steady-state AUC and Cmax of esomeprazole increased by 70% and 18%, respectively, during triple therapy. The increased esomeprazole exposure observed during concomitant use with clarithromycin and amoxicillin is not expected to cause significant safety issues.
The plasma elimination half-life of esomeprazole is approximately 1 to 1.5 hours. Less than 1% of the unchanged drug is excreted in the urine. After oral administration of esomeprazole, approximately 80% is excreted in the urine as inactive metabolites, and the remainder is excreted in the feces as inactive metabolites.
The apparent volume of distribution at steady state in healthy volunteers is approximately 16 liters.
The plasma elimination half-life of esomeprazole is approximately 1 to 1.5 hours. Less than 1% of the unchanged drug is excreted in the urine. After oral administration of esomeprazole, approximately 80% is excreted in the urine as inactive metabolites, and the remainder is excreted in the feces as inactive metabolites.
Esomeprazole binds to plasma proteins at a rate of 97%. Plasma protein binding remains constant within a concentration range of 2 to 20 μmol/L. In healthy volunteers, the steady-state apparent volume of distribution is approximately 16 liters.
Nexium extended-release capsules and Nexium extended-release oral suspension contain bioequivalent esomeprazole magnesium enteric-coated granules. Bioequivalence is based on a single-dose (40 mg) study conducted in 94 healthy male and female volunteers on an empty stomach. Peak plasma concentration (Cmax) occurs at approximately 1.5 hours (Tmax) after oral administration. Cmax increases proportionally with dose, and the area under the plasma concentration-time curve (AUC) triples with increasing dose from 20 mg to 40 mg. Systemic bioavailability is approximately 90% with repeated once-daily administration of 40 mg, compared to approximately 64% with a single 40 mg dose. The mean exposure (AUC) of esomeprazole increased from 4.32 μmol/hr/L on day 1 to 11.2 μmol/hr/L on day 5 after a once-daily administration of 40 mg.

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Metabolism/Metabolites
Esomeprazole is primarily metabolized in the liver via the cytochrome P450 (CYP) enzyme system. Esomeprazole metabolites do not possess antisecretory activity. The majority of esomeprazole metabolism depends on the CYP2C19 isoenzyme, producing hydroxyl and demethylated metabolites. The remainder depends on CYP3A4, producing sulfone metabolites. The CYP2C19 isoenzyme exhibits polymorphism in the metabolism of esomeprazole. Approximately 3% of Caucasians and 15% to 20% of Asians lack CYP2C19 and are termed astomosomal metabolizers. However, the effect of CYP2C19 polymorphism on esomeprazole is less significant than its effect on omeprazole. At steady state, the AUC ratio of astomosomal metabolizers to the AUC ratio of the remaining population (metabolic metabolizers) is approximately 2. After administration of equimolar doses, the S- and R-isomers are metabolized differently in the liver, resulting in higher plasma concentrations of the S-isomer than the R-isomer. Nine major urinary metabolites have been detected. Two of these major metabolites have been identified as hydroxyesomeprazole and its corresponding carboxylic acid. Three major metabolites have been identified in plasma: 5-O-demethyl derivatives, sulfone derivatives, and hydroxyesomeprazole. The major metabolites of esomeprazole have no effect on gastric acid secretion. Esomeprazole is primarily metabolized in the liver via the cytochrome P450 (CYP) enzyme system. Esomeprazole metabolites do not possess antisecretory activity. The majority of esomeprazole metabolism relies on the CYP 2C19 isoenzyme, which produces hydroxyl and demethylated metabolites. The remainder relies on CYP 3A4, which produces sulfone metabolites. CYP 2C19 isoenzymes exhibit polymorphism in esomeprazole metabolism, as approximately 3% of Caucasians and 15% to 20% of Asians lack CYP 2C19 and are termed as poor metabolizers. At steady state, the AUC ratio of poor metabolizers to the AUC ratio of the rest of the population (good metabolizers) is approximately 2. Following equimolar dose administration, the S- and R-isomers are metabolized differently in the liver, resulting in higher plasma concentrations of the S-isomer than the R-isomer.

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Biological half-life
1-1.5 hours

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In Sprague-Dawley rats, oral administration of esomeprazole magnesium (20 mg/kg) via pH-sensitive hydrogel showed a tmax of 2.5 hours, a Cmax of 1.8 μM, an AUC0-24h of 22.6 μM·h, and a terminal half-life (t1/2) of 1.8 hours, with a relative bioavailability of 92% compared to commercially available tablets [2]
-Human plasma protein binding of esomeprazole magnesium was 97% at therapeutic concentrations (based on formulation comparison data in reference [2]) [2]

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Esomeprazole is the S-enantiomer of the proton pump inhibitor omeprazole. Limited information suggests that a mother taking 10 mg of esomeprazole daily, with low concentrations in breast milk, is not expected to have any adverse effects on the breastfed infant.
◉ Effects on Breastfed Infants
One mother took 20 mg of omeprazole orally daily, expressing and discarding breast milk four hours after each morning dose. She then continued breastfeeding for three months until weaning. The infant was in good health at 12 months of age.
A woman with rheumatoid arthritis received oral esomeprazole 10 mg, prednisone 2.5 mg, and sulfasalazine 1 g once daily, along with injections of 200 mg of cetuzumab every two weeks. Her baby was approximately 50% breastfed and 50% formula-fed. No detectable drug-related adverse reactions were observed in the infant.
◉ Effects on Breastfeeding and Lactation
Omeprazole (racemic mixture) has been reported to cause gynecomastia in several men. A retrospective US claims database study found an increased risk of gynecomastia in users of proton pump inhibitors.
A review article reported that a search of the European Pharmacovigilance Center database found 45 cases of gynecomastia, 9 cases of galactorrhea, 19 cases of breast pain, and 12 cases of breast enlargement associated with esomeprazole. A search of the World Health Organization's Global Pharmacovigilance Database found 114 cases of gynecomastia, 38 cases of galactorrhea, 56 cases of breast pain, and 28 cases of breast enlargement associated with esomeprazole.
One woman developed elevated serum prolactin and estradiol levels, along with bilateral galactorrhea, one week after starting esomeprazole 40 mg once daily for the treatment of reflux esophagitis. The galactorrhea disappeared 3 days after esomeprazole was discontinued, and prolactin and estradiol levels returned to normal 7 days after discontinuation. One month later, the patient resumed esomeprazole and experienced bilateral galactorrhea again. She then switched to lansoprazole, and the galactorrhea did not recur. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed. Protein Binding Esomeprazole binds to plasma proteins at a rate of 97%. This binding remains constant within a concentration range of 2 to 20 µmol/L.

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In mice treated with esomeprazole magnesium (20 mg/kg/day for 14 days), no weight loss (<3%) or histopathological abnormalities of the liver, kidneys, stomach or intestines were observed; hematological parameters and liver and kidney function indicators remained within the normal range [1]
-In rats administered esomeprazole magnesium (20 mg/kg) via hydrogel or commercially available tablets, no acute toxic reactions (e.g., vomiting, diarrhea, somnolence) were observed within 24 hours of administration [2]

[1]. Effect of the H, K-ATPase inhibitor, esomeprazole magnesium, on gut total antioxidant capacity in mice. J Nutr Biochem. 2004 Sep;15(9):522-6.

[2]. Preparation and characterization of pH-sensitive methyl methacrylate-g-starch/hydroxypropylated starch hydrogels: in vitro and in vivo study on release of esomeprazole magnesium. Drug Deliv Transl Res. 2015 Jun;5(3):243-56.

[3]. 2013 Annual Meeting. Abstract Supplement.

[4]. Advances in the discovery of exosome inhibitors in cancer. J Enzyme Inhib Med Chem. 2020 Dec;35(1):1322-1330.

Esomeprazole magnesium is a magnesium salt formed by the reaction of magnesium hydroxide with 2 molar equivalents of esomeprazole. It is a gastric acid secretion inhibitor used to treat gastroesophageal reflux disease (GERD), dyspepsia, peptic ulcers, and Zollinger-Ellison syndrome (ZE syndrome). It is an EC 3.6.3.10 (H(+)/K(+) exchange ATPase) inhibitor and an anti-ulcer drug. It contains the esomeprazole (1-) domain. Esomeprazole, marketed as Nexium, is a proton pump inhibitor (PPI) used to treat gastroesophageal reflux disease (GERD), protect the gastric mucosa to prevent recurrence of gastric ulcers or gastric damage caused by long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs), and treat pathological hypersecretion states including ZE syndrome. It is also often used in combination with other antibiotics (such as [DB01060], [DB01211], and [DB00916]) in quadruple therapy for Helicobacter pylori infection. Its efficacy is similar to other PPIs (e.g., [DB00338], [DB00213], [DB00448], [DB05351], and [DB01129]). Esomeprazole is the S-isomer of [DB00338], which is a racemic mixture of the S- and R-enantiomers. In vitro studies have shown that esomeprazole inhibits gastric acid secretion to a similar degree as [DB00338], with no significant difference between the two. Esomeprazole inhibits gastric acid secretion by covalently binding to the cysteine sulfhydryl group on the (H+, K+)-ATPase enzyme on the secretory surface of gastric parietal cells, thus preventing the final step in gastric acid formation. This action results in the inhibition of both basal and stimulant gastric acid secretion, unaffected by stimuli. Because the binding of esomeprazole to (H+, K+)-ATPase is irreversible, new enzyme expression is required to restore gastric acid secretion; therefore, the acid-suppressing effect of esomeprazole lasts for more than 24 hours. Proton pump inhibitors (PPIs) such as esomeprazole have also been shown to inhibit the activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme crucial for cardiovascular health. DDAH inhibition leads to the accumulation of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA), which is believed to be the reason why PPIs are associated with an increased risk of cardiovascular events in patients with unstable coronary syndromes. Due to their good safety profile and the fact that many PPIs are available over-the-counter without a prescription, they are currently widely used in North America. However, long-term use of PPIs (such as esomeprazole) may produce adverse effects, including increased susceptibility to bacterial infections (including Clostridium difficile infection of the gastrointestinal tract), reduced absorption of micronutrients such as iron and vitamin B12, and increased risk of hypomagnesemia and hypocalcemia, all of which may lead to osteoporosis and fractures in later life. Rapid discontinuation of PPIs (such as esomeprazole) may lead to rebound effects and short-term excessive secretion. To prevent rebound effects, the dose of esomeprazole should be slowly reduced or gradually tapered until discontinued. Esomeprazole magnesium is the magnesium salt of esomeprazole, which is the S-isomer of omeprazole and has proton pump inhibitor activity. In the acidic environment of parietal cells, esomeprazole is protonated and converted into an active achiral sulfonamide; the active sulfonamide forms one or more covalent disulfide bonds with the proton pump hydrogen potassium ATPase (H+/K+ ATPase), thereby inhibiting its activity and the secretion of H+ ions from parietal cells into the gastric lumen, the final step in gastric acid production. H+/K+ ATPase is an integrated membrane protein of gastric parietal cells. Esomeprazole is the S-isomer of omeprazole and has proton pump inhibitor activity. In the acidic environment of parietal cells, esomeprazole is protonated and converted into an active achiral sulfinamide; this active sulfinamide forms one or more covalent disulfide bonds with the proton pump hydrogen potassium ATPase (H+/K+ ATPase), thereby inhibiting its activity and preventing parietal cells from secreting H+ ions into the gastric lumen, the final step in gastric acid production. H+/K+ ATPase is an integrated membrane protein of gastric parietal cells. Omeprazole is an S-isomer. See also: esomeprazole (containing the active moiety); esomeprazole magnesium; naproxen (component).

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Drug Indications
Esomeprazole is indicated for the treatment of acid reflux disorders, including healing and maintenance therapy for erosive esophagitis, symptomatic gastroesophageal reflux disease (GERD), peptic ulcers, Helicobacter pylori eradication, prevention of gastrointestinal bleeding induced by nonsteroidal anti-inflammatory drugs (NSAIDs), and long-term treatment of pathological hypersecretion states, including Zollinger-Ellison syndrome.

FDA Label

Nexium Controls is indicated for the short-term treatment of reflux symptoms (e.g., heartburn and acid reflux) in adults.Mechanism of Action
Esomeprazole exerts its inhibitory effect on gastric acid by covalently binding to the cysteine sulfhydryl groups on the secretory surface (H+, K+)-ATPase enzymes of the gastric parietal cells. This action results in the inhibition of both basal and stimulant gastric acid secretion, independent of stimuli.
Because the binding of esomeprazole to (H+, K+)-ATPase is irreversible, new enzymes need to be expressed to restore gastric acid secretion; therefore, the antisecretory effect of esomeprazole lasts for more than 24 hours. Esomeprazole is a proton pump inhibitor that inhibits gastric acid secretion by specifically inhibiting H+/K+-ATPase in gastric parietal cells. The S- and R-isomers of omeprazole are protonated in the acidic environment of parietal cells and converted into the active inhibitor—a chiral sulfonamide. Esomeprazole reduces gastric acidity by specifically acting on the proton pump, blocking the final step in gastric acid production. This effect is dose-dependent, with daily doses up to 20 to 40 mg, and it inhibits gastric acid secretion.

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Esomeprazole magnesium is the S-enantiomer of omeprazole, a proton pump inhibitor (PPI) used clinically to treat acid-related diseases, including gastroesophageal reflux disease (GERD), gastric ulcers, duodenal ulcers, and Helicobacter pylori infection [1][2]. Its core mechanism of action is to irreversibly bind to H+/K+-ATPase in gastric parietal cells under acidic conditions, blocking the secretion of H+ into the gastric lumen, thereby inhibiting gastric acid production [1][2]. In addition to inhibiting gastric acid secretion, it also has other activities: enhancing the total antioxidant capacity of the intestine by upregulating antioxidant enzymes and increasing GSH levels; inhibiting the release of cancer cell exosomes, which may have potential adjuvant antitumor effects [1][4]. It is usually formulated into pH-sensitive preparations (e.g., hydrogels, enteric-coated tablets) to avoid degradation in gastric acid and improve oral bioavailability [2].

C34H36MGN6O6S2

713.12

712.198

161973-10-0

Esomeprazole;119141-88-7;Esomeprazole magnesium trihydrate;217087-09-7;Esomeprazole sodium;161796-78-7;Omeprazole magnesium;95382-33-5;Esomeprazole magnesium salt;1198768-91-0;Esomeprazole potassium salt;161796-84-5;Esomeprazole hemistrontium;914613-86-8

9568613

Light yellow to yellow solid powder

600ºC at 760 mmHg

316.7ºC

2.35E-14mmHg at 25°C

6.789

0

14

10

49

453

2

KWORUUGOSLYAGD-UHFFFAOYSA-N

InChI=1S/2C17H18N3O3S.Mg/c2*1-10-8-18-15(11(2)16(10)23-4)9-24(21)17-19-13-6-5-12(22-3)7-14(13)20-17;/h2*5-8H,9H2,1-4H3;/q2*-1;+2

magnesium;5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ide

2934.99.9001

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, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (2.92 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.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (2.92 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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (2.92 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.

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Solubility in Formulation 4: 1.43 mg/mL (2.01 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)