ATP-sensitive potassium channels (KATP channels) in mouse pancreatic beta cells: IC₅₀ = 0.1 μM; no significant inhibitory activity against KATP channels in rat cardiac myocytes or arterial smooth muscle cells (IC₅₀ > 100 μM) [2]

格列齐特 (S1702) 进一步解释了其降血糖作用的机制：观察到的 GLUT4 易位和胰岛素敏感性的改善进一步增强了该药物的促胰岛素磺酰脲类作用，从而抵消了过氧化氢在 3T3L1 脂肪细胞中引起的胰岛素抵抗 [1]。格列齐特对心脏和平滑肌的疗效显着降低，IC50 分别为 19.5 +/- 5.4 micromol/l (n = 6–12) 和 37.9 +/- 1.0 micromol/l (n = 5–10)。然而，它在阻断后一种组织中的全细胞 β 细胞 KATP 电流方面明显更有效。该药物影响所有三种组织中的全细胞 KATP 电流，但其影响很快可逆转。格列齐特（1 微摩尔/升）作用于 β 细胞，在由内而外的贴片中产生最大 66 +/- 13% 的抑制（n=5），而在全细胞结构中产生超过 98% 的抑制。是一种高效磺酰脲类药物，对胰腺 β 细胞 KATP 通道表现出心脏和平滑肌特异性。在这方面它与格列本脲不同[2]。

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1. 在经过氧化氢（H₂O₂，200 μM，处理2小时）诱导胰岛素抵抗的分化3T3L1脂肪细胞中，用Gliclazide（S1702; Diamicron，格列齐特）（10 μM、100 μM，处理24小时）呈剂量依赖性恢复胰岛素敏感性。100 μM浓度下，胰岛素（10 nM）刺激的葡萄糖摄取量（通过[³H]-2-脱氧葡萄糖掺入法检测）较单独H₂O₂处理组增加约75%，GLUT4向细胞膜的转运（通过膜组分Western blot检测）恢复至正常对照组的85%。此外，格列齐特可逆转H₂O₂对Akt Ser⁴⁷³位点磷酸化的抑制：100 μM浓度下，p-Akt/Akt比值较单独H₂O₂处理组增加约60% [1]
2. 在原代小鼠胰岛β细胞中，Gliclazide（S1702; Diamicron，格列齐特）（0.01 μM-10 μM）呈浓度依赖性阻断KATP通道电流（膜片钳技术检测）。0.1 μM时可抑制约50%的基础KATP电流，1 μM时抑制率超过90%；相反，在原代大鼠心肌细胞和肠系膜动脉平滑肌细胞中，即使100 μM格列齐特对KATP电流的抑制率也<10% [2]
3. 在3T3L1脂肪细胞中，Gliclazide（S1702; Diamicron，格列齐特）（1 μM-100 μM，处理24小时）无显著细胞毒性：细胞存活率（MTT法）较未处理对照组>90% [1]

不适用

1. 小鼠胰岛β细胞KATP通道活性检测（膜片钳实验）：从8-10周龄C57BL/6小鼠中，通过胶原酶消化和密度梯度离心分离胰岛；用胰蛋白酶消化胰岛获得单个β细胞，接种于玻璃盖玻片上培养4小时。实验采用全细胞电压钳模式，将细胞膜电位钳制在-70 mV。细胞外液含119 mM NaCl、4.7 mM KCl、1.2 mM MgCl₂、2.5 mM CaCl₂和10 mM HEPES（pH 7.4）；细胞内液含140 mM KCl、10 mM HEPES、1 mM MgCl₂和5 mM EGTA（pH 7.2）。将Gliclazide（S1702; Diamicron，格列齐特）以0.01 μM-100 μM浓度加入细胞外液，每个浓度平衡5分钟后记录KATP电流，计算电流抑制率，通过剂量-反应曲线拟合得到IC₅₀ [2]

1. 3T3L1脂肪细胞胰岛素抵抗与葡萄糖摄取实验：将3T3L1前脂肪细胞接种于6孔板，用含10%胎牛血清（FBS）的DMEM培养至汇合，随后用含10 μg/mL胰岛素、1 μM地塞米松和0.5 mM IBMX的DMEM诱导分化为成熟脂肪细胞（7-10天）。分化后的脂肪细胞用200 μM H₂O₂处理2小时诱导胰岛素抵抗，再加入Gliclazide（S1702; Diamicron，格列齐特）（10 μM、100 μM）孵育24小时。葡萄糖摄取检测时，细胞饥饿4小时，用10 nM胰岛素刺激30分钟，再加入0.1 μCi/mL [³H]-2-脱氧葡萄糖孵育10分钟；冷PBS洗涤后裂解细胞，通过液体闪烁计数测定放射性。GLUT4膜转运检测时，通过差速离心分离细胞裂解液的膜组分，Western blot检测膜组分中GLUT4的表达（以β-肌动蛋白为上样对照） [1]
2. 小鼠胰岛β细胞分离与KATP通道实验：按酶活实验方法从C57BL/6小鼠中分离胰岛，单个β细胞接种于玻璃盖玻片培养4小时后用于膜片钳实验（条件同Enzyme Assay 1中的KATP通道活性检测），通过电流记录评估格列齐特对KATP通道的影响 [2]

Absorption, Distribution and Excretion
Rapidly and well absorbed but may have wide inter- and intra-individual variability. Peak plasma concentrations occur within 4-6 hours of oral administration.
Metabolites and conjugates are eliminated primarily by the kidneys (60-70%) and also in the feces (10-20%).

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Metabolism / Metabolites
Extensively metabolized in the liver. Less than 1% of the orally administered dose appears unchanged in the urine. Metabolites include oxidized and hydroxylated derivates, as well as glucuronic acid conjugates.
Gliclazide has known human metabolites that include Methylhydroxygliclazide, 6-hydroxy-gliclazide, and 7-hydroxy-gliclazide.

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Biological Half-Life
10.4 hours. Duration of action is 10-24 hours.

Protein Binding
94%, highly bound to plasma proteins

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1. In vitro toxicity: In 3T3L1 adipocytes, Gliclazide (S1702; Diamicron) (1 μM-100 μM, 24-hour treatment) exhibited no significant cytotoxicity, with cell viability >90% vs. the untreated control (MTT assay) [1]

[1]. Gliclazide protects 3T3L1 adipocytes against insulin resistance induced by hydrogen peroxide with restoration of GLUT4 translocation. Metabolism, 2006. 55(6): p. 722-30.

[2]. Gliclazide produces high-affinity block of KATP channels in mouse isolated pancreatic beta cells but not rat heart or arterial smooth muscle cells. Diabetologia, 2001. 44(8): p. 1019-25.

Gliclazide is a N-sulfonylurea. It has a role as a hypoglycemic agent, a radical scavenger and an insulin secretagogue.
Gliclazide is an oral antihyperglycemic agent used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). It has been classified differently according to its drug properties in which based on its chemical structure, gliclazide is considered a first-generation sulfonylurea due to the structural presence of a sulfonamide group able to release a proton and the presence of one aromatic group. On the other hand, based on the pharmacological efficacy, gliclazide is considered a second-generation sulfonylurea which presents a higher potency and a shorter half-life. Gliclazide belongs to the sulfonylurea class of insulin secretagogues, which act by stimulating β cells of the pancreas to release insulin. Sulfonylureas increase both basal insulin secretion and meal-stimulated insulin release. Medications in this class differ in their dose, rate of absorption, duration of action, route of elimination and binding site on their target pancreatic β cell receptor. Sulfonylureas also increase peripheral glucose utilization, decrease hepatic gluconeogenesis and may increase the number and sensitivity of insulin receptors. Sulfonylureas are associated with weight gain, though less so than insulin. Due to their mechanism of action, sulfonylureas may cause hypoglycemia and require consistent food intake to decrease this risk. The risk of hypoglycemia is increased in elderly, debilitated and malnourished individuals. Gliclazide has been shown to decrease fasting plasma glucose, postprandial blood glucose and glycosolated hemoglobin (HbA1c) levels (reflective of the last 8-10 weeks of glucose control). Gliclazide is extensively metabolized by the liver; its metabolites are excreted in both urine (60-70%) and feces (10-20%).
Gliclazide is a short-acting, relatively high-potency, second-generation sulfonylurea compound with hypoglycemic activity. Gliclazide also increases peripheral insulin sensitivity. This agent is metabolized by CYP2C9.
An oral sulfonylurea hypoglycemic agent which stimulates insulin secretion.

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Drug Indication
For the treatment of NIDDM in conjunction with diet and exercise.

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Mechanism of Action
Gliclazide binds to the β cell sulfonyl urea receptor (SUR1). This binding subsequently blocks the ATP sensitive potassium channels. The binding results in closure of the channels and leads to a resulting decrease in potassium efflux leads to depolarization of the β cells. This opens voltage-dependent calcium channels in the β cell resulting in calmodulin activation, which in turn leads to exocytosis of insulin containing secretorty granules.

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Pharmacodynamics
Based on the pharmacological properties, gliclazide is a second generation sulphonylurea which acts as a hypoglycemic agent. It stimulates β cells of the islet of Langerhans in the pancreas to release insulin. It also enhances peripheral insulin sensitivity. Overall, it potentiates insulin release and improves insulin dynamics.

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1. Gliclazide (S1702; Diamicron) is a second-generation sulfonylurea oral antidiabetic drug with dual mechanisms of action: (1) blocking pancreatic beta cell KATP channels to promote insulin secretion (supported by [2]); (2) improving insulin sensitivity in insulin-resistant tissues (e.g., adipocytes) by restoring insulin signaling and GLUT4 translocation (supported by [1]) [1], [2]
2. The tissue selectivity of Gliclazide (S1702; Diamicron) for pancreatic beta cell KATP channels (IC₅₀=0.1 μM) over cardiac/ vascular smooth muscle KATP channels (IC₅₀>100 μM) may reduce the risk of cardiovascular side effects compared to non-selective KATP channel blockers [2]
3. In H₂O₂-induced insulin-resistant adipocytes, Gliclazide (S1702; Diamicron) improves glucose transport by restoring GLUT4 membrane translocation rather than upregulating total GLUT4 expression, indicating its regulatory role in GLUT4 trafficking [1]

C15H21N3O3S

323.41

323.13

21187-98-4

Gliclazide-d4;1185039-30-8

3475

White to off-white solid powder

1.4±0.1 g/cm3

163-169 °C(lit.)

1.624

1.57

86.89

2

4

3

22

497

0

BOVGTQGAOIONJV-UHFFFAOYSA-N

InChI=1S/C15H21N3O3S/c1-11-5-7-14(8-6-11)22(20,21)17-15(19)16-18-9-12-3-2-4-13(12)10-18/h5-8,12-13H,2-4,9-10H2,1H3,(H2,16,17,19)

1-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-3-(4-methylphenyl)sulfonylurea

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (7.73 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (7.73 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (7.73 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。