ATP-sensitive potassium (KATP) channels on pancreatic β-cells [1]

Repaglinide decreases postprandial glucose levels by boosting the early phase of insulin secretion and increasing the total quantity of insulin secreted[1].

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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]

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.

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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]

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]

Rats

Absorption, Distribution and Excretion
Rapid and complete absorption after oral administration. Peak plasma concentrations occur within 1 hour (range 0.5–1.4 hours). Absolute bioavailability is approximately 56%. Maximum biological effect occurs within 3–3.5 hours, with plasma insulin levels remaining elevated for 4–6 hours. The area under the curve (AUC) after a single 2 mg dose of repaglinide in healthy subjects was 18.0–18.7 (ng/mL/h)^3. 90% is excreted in feces (<2% is the original drug), and 8% is excreted in urine (0.1% is the original drug). Blood flow rate after intravenous administration in healthy individuals is 31 L. Blood flow rate after intravenous administration is 33–38 L/hour. Metabolism/Metabolites Repaglinide is rapidly metabolized via oxidation and dealkylation at cytochrome P450 3A4 and 2C9, yielding the major dicarboxylic acid derivative (M2). Further oxidation produces an aromatic amine derivative (M1). Glucuronization of the carboxylic acid group of repaglinide yields acyl glucuronide (M7). Several other unidentified metabolites have been detected. Repaglinide metabolites do not exhibit significant hypoglycemic activity.
The known metabolites of repaglinide include: repaglinide aromatic amine, 2-ethoxy-4-[2-[[1-[2-(4-hydroxybutylamino)phenyl]-3-methylbutyl]amino]-2-oxoethyl]benzoic acid, 3'-hydroxyrepaglinide (a 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.

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Biological half-life
1 hour

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Absorption: Oral repaglinide (AG-EE 623ZW) is rapidly absorbed, reaching peak plasma concentration within 1 hour after administration; oral bioavailability is approximately 56-60%[1]
-Distribution: The volume of distribution of this drug in the human body is 0.1 L/kg, mainly distributed in pancreatic β cells[1]
-Metabolism: Mainly metabolized in the liver by cytochrome P450 3A4 (CYP3A4) and CYP2C8 into inactive metabolites[1]
-Excretion: Approximately 90% of the metabolites are excreted in feces, and 10% in urine; less than 1% of the original drug is excreted unchanged[1]
-Half-life: The elimination half-life in the human body is 1-1.5 hours[1]

Hepatotoxicity
In multiple large clinical trials, elevated serum transaminases during repaglinide treatment were uncommon and occurred at a similar rate to the placebo group. All elevated serum enzymes were asymptomatic and returned to normal rapidly after discontinuation of the drug. Since repaglinide was approved and widely used, a small number of clinically significant cases of liver injury have been reported. Liver injury occurred within 2 to 8 weeks, and the pattern of elevated serum enzymes was typically cholestatic or mixed. Jaundice and pruritus were common. No immune allergic reactions or autoantibodies were observed. All published cases were self-limiting, resolving within 1 to 2 months after discontinuation of the drug. Probability score: D (likely a rare cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information regarding the use of repaglinide during lactation. Repaglinide is a weak acid with a protein binding rate exceeding 98%, therefore it is unlikely to enter breast milk in clinically significant amounts. Monitor breastfed infants for signs of hypoglycemia, such as irritability, lethargy, feeding difficulties, seizures, cyanosis, apnea, or hypothermia. If there is any concern, monitoring the breastfed infant's blood glucose levels is recommended while the mother is receiving repaglinide treatment. However, especially in newborns or preterm infants, alternative medications may be preferred.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
>98% (e.g., binding to albumin and α1-acid glycoprotein)

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Plasma protein binding rate: Repaglinide (AG-EE 623ZW) is highly bound to plasma proteins in the human body (98%)[1]
- Hypoglycemia: The most common side effect, occurring in 15-20% of clinical trials; the risk is higher in elderly patients or those with irregular eating habits[1]
- Hepatotoxicity and nephrotoxicity: No significant reports of hepatotoxicity or nephrotoxicity have been seen at therapeutic doses; no dose adjustment is required in patients with mild to moderate renal impairment[1]
- Drug interactions: CYP3A4 inhibitors (e.g., ketoconazole, erythromycin) and CYP2C8 inhibitors (e.g., gemfibrozil) can increase plasma concentrations of repaglinide, thereby increasing the risk of hypoglycemia[1]
- Other side effects: Rare adverse reactions include headache, dizziness, nausea, and diarrhea, which are usually mild and transient[1]

[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.

Pharmacodynamics
Insulin secretion by pancreatic β cells is partially regulated by cell membrane potential. Membrane potential is regulated by the inverse relationship between the activity of ATP-sensitive potassium channels (ABCC8) and extracellular glucose concentration. Extracellular glucose enters the cell via the GLUT2 (SLC2A2) transporter. After entering the cell, glucose is metabolized to produce ATP. High concentrations of ATP inhibit ATP-sensitive potassium channels, leading to membrane depolarization. When the extracellular glucose concentration is low, ATP-sensitive potassium channels open, leading to membrane repolarization. High concentrations of glucose cause ATP-sensitive potassium channels to close, causing membrane depolarization and opening L-type calcium channels. Calcium ion influx stimulates calcium-dependent insulin granule exocytosis. Repaglinide increases insulin release by glucose-dependently inhibiting ATP-sensitive potassium channels.

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Repaglinide (AG-EE 623ZW) is a meglitinide antidiabetic drug that has been clinically approved for the treatment of type 2 diabetes[1].
- Its core hypoglycemic mechanism involves rapidly and reversibly shutting down KATP channels on pancreatic β cells, thereby promoting glucose-dependent insulin secretion [1].
- The drug has a rapid onset of action and a short duration of action, and needs to be taken before meals to effectively control postprandial hyperglycemia [1].
- Due to its short half-life and low risk of persistent hypoglycemia, it is suitable for type 2 diabetic patients who cannot tolerate sulfonylureas or have irregular meal times [1].

C27H36N2O4

452.59

452.267

135062-02-1

Repaglinide-d5;1217709-85-7

65981

White to off-white solid powder

1.1±0.1 g/cm3

672.9±55.0 °C at 760 mmHg

129-130.2 °C

360.8±31.5 °C

0.0±2.2 mmHg at 25°C

1.568

4.69

2

5

10

33

619

1

CCOC1=C(C=CC(=C1)CC(=O)N[C@@H](CC(C)C)C2=CC=CC=C2N3CCCCC3)C(=O)O

FAEKWTJYAYMJKF-QHCPKHFHSA-N

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

2-ethoxy-4-[2-[[(1S)-3-methyl-1-(2-piperidin-1-ylphenyl)butyl]amino]-2-oxoethyl]benzoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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: ≥ 2.5 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.

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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.

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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.

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