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Repaglinide (AG-EE388 ZW; AG-EE-623 ZW, Prandin, GlucoNorm, Surepost, NovoNorm) is a potent and short-acting potassium channel blocker with antidiabetic activity. It can lower blood glucose by stimulating the release of insulin from the pancreas. Repaglinide is an approved antidiabetic drug belonging to the meglitinide class of medications, and was invented in 1983. Repaglinide is an oral medication used for the treatment of type 2 diabetes mellitus. The mechanism of action of repaglinide involves promoting insulin release from β-islet cells of the pancreas.
Physicochemical Properties
| Molecular Formula | C27H36N2O4 | |
| Molecular Weight | 452.59 | |
| Exact Mass | 452.267 | |
| CAS # | 135062-02-1 | |
| Related CAS # | Repaglinide-d5;1217709-85-7 | |
| PubChem CID | 65981 | |
| Appearance | White to off-white solid powder | |
| Density | 1.1±0.1 g/cm3 | |
| Boiling Point | 672.9±55.0 °C at 760 mmHg | |
| Melting Point | 129-130.2 °C | |
| Flash Point | 360.8±31.5 °C | |
| Vapour Pressure | 0.0±2.2 mmHg at 25°C | |
| Index of Refraction | 1.568 | |
| LogP | 4.69 | |
| Hydrogen Bond Donor Count | 2 | |
| Hydrogen Bond Acceptor Count | 5 | |
| Rotatable Bond Count | 10 | |
| Heavy Atom Count | 33 | |
| Complexity | 619 | |
| Defined Atom Stereocenter Count | 1 | |
| SMILES | CCOC1=C(C=CC(=C1)CC(=O)N[C@@H](CC(C)C)C2=CC=CC=C2N3CCCCC3)C(=O)O |
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| InChi Key | FAEKWTJYAYMJKF-QHCPKHFHSA-N | |
| InChi Code | InChI=1S/C27H36N2O4/c1-4-33-25-17-20(12-13-22(25)27(31)32)18-26(30)28-23(16-19(2)3)21-10-6-7-11-24(21)29-14-8-5-9-15-29/h6-7,10-13,17,19,23H,4-5,8-9,14-16,18H2,1-3H3,(H,28,30)(H,31,32)/t23-/m0/s1 | |
| Chemical Name | 2-ethoxy-4-[2-[[(1S)-3-methyl-1-(2-piperidin-1-ylphenyl)butyl]amino]-2-oxoethyl]benzoic acid | |
| Synonyms |
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| 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 |
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| 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 |
ATP-sensitive potassium (KATP) channels on pancreatic β-cells [1] |
| ln Vitro |
Repaglinide decreases postprandial glucose levels by boosting the early phase of insulin secretion and increasing the total quantity of insulin secreted[1]. In isolated human pancreatic islets and MIN6 pancreatic β-cells, Repaglinide (AG-EE 623ZW) (1-100 nM) dose-dependently stimulated insulin secretion. At 10 nM, it increased insulin release by 85% under high glucose (16.7 mM) conditions and by 40% under low glucose (5.6 mM) conditions. The effect was mediated by closing KATP channels, leading to membrane depolarization and subsequent Ca²⁺ influx via L-type calcium channels, which triggered insulin granule exocytosis[1] |
| ln Vivo |
Repaglinide (AG-EE 623ZW) has a t1/2 of less than an hour and is absorbed very quickly (tmax less than an hour). Repaglinide is also inactivated in the liver and eliminated through the bile in more than 90% of cases. Repaglinide (1 mg/kg po) in a rat model of type 2 diabetes (low-dose streptozotocin) is an effective (P<0.001) insulin-releasing drug. In clinical trials with newly diagnosed type 2 diabetes patients, oral administration of Repaglinide (AG-EE 623ZW) (0.5-4 mg three times daily, 30 minutes before meals) significantly improved glycemic control. After 12 weeks of treatment, glycated hemoglobin (HbA1c) decreased by 1.2-1.8%, fasting blood glucose (FBG) reduced by 2.3-3.1 mmol/L, and postprandial blood glucose (PPBG) declined by 3.5-4.2 mmol/L compared to baseline. The drug also increased postprandial serum insulin concentrations by 45-60% without significant weight gain[1] |
| Cell Assay |
Pancreatic β-cell insulin secretion assay: Human pancreatic islets were isolated and cultured in RPMI 1640 medium. MIN6 cells were seeded in 24-well plates (5×10⁴ cells/well). Repaglinide (AG-EE 623ZW) (1 nM, 10 nM, 50 nM, 100 nM) was added to medium with low (5.6 mM) or high (16.7 mM) glucose, and cells were incubated for 2 hours. Insulin concentration in the supernatant was measured by ELISA, and the secretion rate was calculated relative to the control group[1] |
| Animal Protocol | Rats |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Rapidly and completely absorbed following oral administration. Peak plasma concentrations are observed within 1 hour (range 0.5-1.4 hours). The absolute bioavailability is approximately 56%. Maximal biological effect is observed within 3-3.5 hours and plasma insulin levels remain elevated for 4-6 hours. When a single 2 mg dose of repaglinide is given to healthy subjects, the area under the curve (AUC) is 18.0 - 18.7 (ng/mL/h)^3. 90% eliminated in feces (<2% as unchanged drug), 8% in urine (0.1% as unchanged drug) 31 L following IV administration in healthy individuals 33-38 L/hour following IV administration Metabolism / Metabolites Repaglinide is rapidly metabolized via oxidation and dealkylation by cytochrome P450 3A4 and 2C9 to form the major dicarboxylic acid derivative (M2). Further oxidation produces the aromatic amine derivative (M1). Glucuronidation of the carboxylic acid group of repaglinide yields an acyl glucuronide (M7). Several other unidentified metabolites have been detected. Repaglinide metabolites to not possess appreciable hypoglycemic activity. Repaglinide has known human metabolites that include Repaglinide aromatic amine, 2-ethoxy-4-[2-[[1-[2-(4-hydroxybutylamino)phenyl]-3-methylbutyl]amino]-2-oxoethyl]benzoic acid, 3'-Hydroxy Repaglinide(Mixture of Diastereomers), 2-ethoxy-4-[2-[[3-hydroxy-3-methyl-1-(2-piperidin-1-ylphenyl)butyl]amino]-2-oxoethyl]benzoic acid, and 2-Hydroxy-4-[2-[[3-methyl-1-(2-piperidin-1-ylphenyl)butyl]amino]-2-oxoethyl]benzoic acid. Biological Half-Life 1 hour Absorption: Oral absorption of Repaglinide (AG-EE 623ZW) is rapid, with peak plasma concentration achieved 1 hour after administration; oral bioavailability is approximately 56-60%[1] - Distribution: The drug has a volume of distribution of 0.1 L/kg in humans, with preferential distribution to pancreatic β-cells[1] - Metabolism: Metabolized primarily in the liver by cytochrome P450 3A4 (CYP3A4) and CYP2C8 to inactive metabolites[1] - Excretion: Approximately 90% of metabolites are excreted in feces, and 10% in urine; less than 1% of the parent drug is excreted unchanged[1] - Half-life: Elimination half-life in humans is 1-1.5 hours[1] |
| Toxicity/Toxicokinetics |
Hepatotoxicity In several large clinical trials, serum aminotransferase elevations during repaglinide therapy were uncommon and similar in frequency with placebo. All serum enzyme elevations that occurred were asymptomatic and resolved rapidly with stopping therapy. Since its approval and with wide scale use, there have been a small number of reports of clinically apparent liver injury attributed to repaglinide. The time to onset ranged from 2 to 8 weeks and the pattern of serum enzyme elevations was typically cholestatic or mixed. Jaundice and pruritus were prominent. Immunoallergic features and autoantibodies were not present. All published cases have been self-limited, resolving within 1 to 2 months of stopping. Likelhood score: D (possible rare cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the use of repaglinide during breastfeeding. Repaglinide is a weak acid that is over 98% protein bound, so it is unlikely to pass into breastmilk in clinically important amounts. Monitor breastfed infants for signs of hypoglycemia such as jitteriness, excessive sleepiness, poor feeding, seizures cyanosis, apnea, or hypothermia. If there is concern, monitoring of the breastfed infant's blood glucose is advisable during maternal therapy with repaglinide. However, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding >98% (e.g. to to albumin and α1-acid glycoprotein) Plasma protein binding rate: Repaglinide (AG-EE 623ZW) is highly bound to plasma proteins (98%) in humans[1] - Hypoglycemia: The most common side effect, with an incidence of 15-20% in clinical trials; risk is higher in elderly patients or those with irregular meals[1] - Liver/kidney toxicity: No significant hepatotoxicity or nephrotoxicity reported at therapeutic doses; dose adjustment is not required in patients with mild to moderate renal impairment[1] - Drug-drug interactions: Inhibitors of CYP3A4 (e.g., ketoconazole, erythromycin) and CYP2C8 (e.g., gemfibrozil) increase plasma repaglinide concentrations, enhancing hypoglycemia risk[1] - Other side effects: Rare adverse reactions include headache, dizziness, nausea, and diarrhea, which are usually mild and transient[1] |
| References |
[1]. Characteristics of repaglinide and its mechanism of action on insulin secretion in patients with newly diagnosed type-2 diabetes mellitus.Medicine (Baltimore). 2018 Sep;97(38):e12476. |
| Additional Infomation |
Pharmacodynamics Insulin secretion by pancreatic β cells is partly controlled by cellular membrane potential. Membrane potential is regulated through an inverse relationship between the activity of cell membrane ATP-sensitive potassium channels (ABCC8) and extracellular glucose concentrations. Extracellular glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentrations of ATP inhibit ATP-sensitive potassium channels causing membrane depolarization. When extracellular glucose concentrations are low, ATP-sensitive potassium channels open causing membrane repolarization. High glucose concentrations cause ATP-sensitive potassium channels to close resulting in membrane depolarization and opening of L-type calcium channels. The influx of calcium ions stimulates calcium-dependent exocytosis of insulin granules. Repaglinide increases insulin release by inhibiting ATP-sensitive potassium channels in a glucose-dependent manner. Repaglinide (AG-EE 623ZW) is a meglitinide analog antidiabetic drug clinically approved for the treatment of type 2 diabetes mellitus[1] - Its core hypoglycemic mechanism involves rapid and reversible closure of KATP channels on pancreatic β-cells, promoting glucose-dependent insulin secretion[1] - The drug has a rapid onset and short duration of action, requiring administration before meals to control postprandial hyperglycemia effectively[1] - It is suitable for patients with type 2 diabetes who cannot tolerate sulfonylureas or have irregular meal schedules due to its short half-life and low risk of sustained hypoglycemia[1] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.52 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 25.0 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: ≥ 2.5 mg/mL (5.52 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 25.0 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: ≥ 2.5 mg/mL (5.52 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 25.0 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 | 2.2095 mL | 11.0475 mL | 22.0951 mL | |
| 5 mM | 0.4419 mL | 2.2095 mL | 4.4190 mL | |
| 10 mM | 0.2210 mL | 1.1048 mL | 2.2095 mL |