ATP-sensitive K+ channel (KATP)

格列本脲（棕色脂肪细胞；10 μM；1 天）对脂肪细胞分化没有影响。格列本脲（Ucp1-2A-GFP 棕色脂肪细胞）可显着增加 UCP1 表达。格列本脲直接结合并抑制 ATP 依赖性钾通道 (KATP) 的 SUR1 亚基，从而促进胰腺 β 细胞产生胰岛素 [2]。格列本脲通过允许 Cl- 进入线粒体内膜并促进线粒体网络中的 Cl-/K+ 共转运来干扰线粒体生物能 [4]。格列本脲诱导的自噬限制了其对 β 细胞胰岛素分泌的有益作用 [5]。

格列本脲（2 mg/kg；口服）可快速降低血糖水平并增强胰岛素的释放[2]。使用格列本脲（50 μg/kg；口服）时，体重和身体成分不会显着改变[2]。
格列本脲（是目前用于治疗2型糖尿病的美国食品药品监督管理局批准的药物之一，可以显著增强棕色和白色脂肪细胞中UCP1的表达。格列本脲喂养的小鼠对高脂饮食诱导的肥胖表现出明显的抵抗力，降低了血液甘油三酯水平，增加了棕色脂肪组织中UCP1的表达。此外，腹股沟白色脂肪组织原位注射优降糖显著增强了UCP1的表达，增加了产热。进一步的机制研究表明，格列本脲对脂肪细胞UCP1表达的影响是KATP通道无关的，但可能涉及Ca2+-钙调神经磷酸酶NFAT信号通路的调节。总的来说，我们的研究结果揭示了格列本脲/优降糖在调节脂肪细胞中UCP1表达和产热方面的显著作用，这可能被重新用于治疗肥胖。[2]

众所周知，格列本脲与磺脲受体（SUR）相互作用，最近已被证明可以抑制囊性纤维化跨膜电导调节蛋白（CFTR），这两种蛋白都是ABC[腺苷5'-三磷酸（ATP）结合盒]转运蛋白的成员。研究了格列本脲和两种合成的磺酰基氰基胍衍生物（称为BM-208和BM-223）对P-糖蛋白的影响，P-糖蛋白是导致癌症细胞多药耐药性（MDR）的主要ABC转运蛋白。为此，我们采用了不同的细胞系，这些细胞系表达或不表达P-糖蛋白，如蛋白质印迹所证实的：首先，一种肿瘤细胞系（VBL600），选自急性白血病衍生的人类T细胞系（CEM）；第二，来源于大鼠结肠腺癌的上皮细胞系（CC531（mdr+）），最后，来源于负鼠肾近端小管的非肿瘤上皮细胞系。格列本脲和两种相关衍生物抑制P-糖蛋白，因为首先，它们仅在P-糖蛋白表达细胞系中急性增加[3H]秋水仙碱的积累；其次，BM-223通过增强秋水仙碱、紫杉醇和长春花碱的细胞毒性逆转了MDR现象，与维拉帕米非常相似；第三，BM-208和BM-223阻断了[3H]叠氮平对P-糖蛋白的光亲和标记。此外，格列本脲本身就是P-糖蛋白的底物，因为[3H]格列本脲的细胞积累较低，并且仅在表达P-糖蛋白的细胞系中添加P-糖蛋白底物（如长春花碱和环孢菌素）会显著增加。我们得出结论，格列本脲和两种磺酰基氰基胍衍生物抑制P-糖蛋白，磺酰脲类药物似乎是ABC转运蛋白的一般抑制剂，这表明它们与一些保守的基序相互作用。[3]

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通过大鼠肝线粒体在乙酸钾、硝酸钾和氯化钾介质中的被动渗透肿胀、氧气消耗和线粒体跨膜电位（Deltapsi），评估了抗糖尿病磺酰脲类药物格列本脲对线粒体生物能量学的干扰。格列本脲不会使线粒体内膜透性为H+，但会通过打开线粒体内阴离子通道（IMAC）诱导对Cl-的透性。格列本脲诱导的Cl-内流促进K+进入线粒体，从而促进Cl-/K+净共转运、Deltapsi消散和刺激状态4呼吸速率。结论是格列本脲通过使线粒体内膜对Cl-渗透并促进线粒体内Cl-/K+的净共转运来干扰大鼠肝脏的线粒体生物能量学，而膜对H+的渗透没有显著变化[4]。

糖尿病是一种代谢性疾病，部分原因是低血糖症，影响世界8%的成年人口。众所周知，格列本脲通过靶向β细胞促进胰岛素分泌。自噬作为细胞的一种自我保护机制已被广泛研究，并在不同的组织或细胞中具有特殊的生理作用。然而，自噬和格列本脲之间的相互作用尚不清楚。在这项研究中，我们研究了自噬在格列本脲诱导的胰腺β细胞胰岛素分泌中的作用。在此，我们发现格列本脲促进胰岛素释放，并通过腺苷5'-单磷酸（AMP）激活蛋白激酶（AMPK）途径进一步激活MIN-6细胞的自噬。自噬抑制剂3-甲基腺嘌呤（3-MA）对自噬的抑制进一步增强了格列本脲的分泌功能。这些结果表明，格列本脲诱导的自噬通过激活AMPK通路而不是改变雷帕霉素（mTOR）的哺乳动物靶点，在促进胰岛素分泌方面起着抑制作用[5]。

Animal/Disease Models: Mice[2]
Doses: 2 mg/kg
Route of Administration: Po
Experimental Results: Increased of insulin release and rapid drop of blood glucose level.

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Identification of safe and effective compounds to increase or activate UCP1 expression in brown or white adipocytes remains a potent therapeutic strategy to combat obesity. Here we reported that, glyburide, one of the FDA-approved drugs currently used to treat type 2 diabetes, can significantly enhance UCP1 expression in both brown and white adipocytes. Glyburide-fed mice exhibited a clear resistance to high-fat diet-induced obesity, reduced blood triglyceride level, and increased UCP1 expression in brown adipose tissue. Moreover, in situ injection of glyburide to inguinal white adipose tissue remarkably enhanced UCP1 expression and increased thermogenesis. Further mechanistic studies indicated that the glyburide effect in UCP1 expression in adipocytes was KATP channel independent but may involve the regulation of the Ca2+-Calcineurin-NFAT signal pathway. Overall, our findings revealed the significant effects of glyburide in regulating UCP1 expression and thermogenesis in adipocytes, which can be potentially repurposed to treat obesity.[2]

Absorption, Distribution and Excretion
Elderly patients taking glyburide reached a Cmax of 211-315ng/mL with a Tmax of 0.9-1.0h, while younger patients reached a Cmax of 144-302ng/mL with a Tmax of 1.3-3.0h. Patients taking glyburide have and AUC of 348ng*h/mL.
Unlike other sulfonylureas, glyburide is 50% excreted in the urine and 50% in the feces. Glyburide is mainly excreted as the metabolite 4-trans-hydroxyglyburide.
Elderly patients have a volume of distribution of 19.3-52.6L, while younger patients have a volume of distribution of 21.5-49.3L.
Elderly patients have a clearance of 2.70-3.55L/h, while younger patients have a clearance of 2.47-4.11L/h.

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Metabolism / Metabolites
Glyburide is metabolized mainly by CYP3A4, followed by CYP2C9, CYP2C19, CYP3A7, and CYP3A5. These enzymes metabolize glyburide to 4-trans-hydroxycyclohexyl glyburide (M1), 4-cis-hydroxycyclohexyl glyburide (M2a), 3-cis-hydroxycyclohexyl glyburide (M2b), 3-trans-hydroxycyclohexyl glyburide (M3), 2-trans-hydroxycyclohexyl glyburide (M4), and ethylhydroxycyclohexyl glyburide (M5). The M1 and M2b metabolites are considered active, along with the parent molecule.
Glyburide has known human metabolites that include 3-cis-Hydroxycyclohexyl glyburide, 3-trans-Hydroxycyclohexyl glyburide, 2-trans-hydroxycyclohexyl glyburide, and 4-cis-hydroxycyclohexyl glyburide.

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Biological Half-Life
Elderly patients have a terminal elimination half life of 4.0-13.4h, while younger patients have a terminal elimination half life of 4.0-13.9h.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited data indicate that the levels of glyburide in milk are negligible. 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 hypoglycemic agents.
◉ Effects in Breastfed Infants
The blood glucose level was normal in one breastfed infant whose mothers was taking oral glyburide 5 mg daily.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Glyburide is 99.9% bound to protein in plasma with >98% accounted for by binding to serum albumin.

[1]. The anti-diabetic drug trelagliptin induces vasodilation via activation of Kv channels and SERCA pumps. Life Sci. 2021;283:119868.

[2]. Glyburide Regulates UCP1 Expression in Adipocytes Independent of KATP Channel Blockade. iScience. 2020;23(9):101446.

[3]. P-glycoprotein inhibition by glibenclamide and related compounds. Pflugers Arch. 1999;437(5):652-660.

[4]. Glibenclamide interferes with mitochondrial bioenergetics by inducing changes on membrane ion permeability. J Biochem Mol Toxicol. 2004;18(3):162-169.

[5]. Glibenclamide-Induced Autophagy Inhibits Its Insulin Secretion-Improving Function in β Cells. Int J Endocrinol. 2019;2019:1265175.

Glyburide is an N-sulfonylurea that is acetohexamide in which the acetyl group is replaced by a 2-(5-chloro-2-methoxybenzamido)ethyl group. It has a role as a hypoglycemic agent, an anti-arrhythmia drug, an EC 2.7.1.33 (pantothenate kinase) inhibitor and an EC 3.6.3.49 (channel-conductance-controlling ATPase) inhibitor. It is a N-sulfonylurea and a member of monochlorobenzenes.
Glyburide is a second generation sulfonylurea used to treat patients with diabetes mellitus type II. It is typically given to patients who cannot be managed with the standard first line therapy, [metformin]. Glyburide stimulates insulin secretion through the closure of ATP-sensitive potassium channels on beta cells, raising intracellular potassium and calcium ion concentrations. Glyburide was granted FDA approval on 1 May 1984. A formulation with metformin was granted FDA approval on on 31 July 2000.
Glyburide is a Sulfonylurea.
Glyburide is a sulfonamide urea derivative with antihyperglycemic activity that can potentially be used to decrease cerebral edema. Upon administration, glyburide binds to and blocks the sulfonylurea receptor type 1 (SUR1) subunit of the ATP-sensitive inwardly-rectifying potassium (K(ATP)) channels on the membranes of pancreatic beta cells. This prevents the inward current flow of positively charged potassium (K+) ions into the cell, and induces a calcium ion (Ca2+) influx through voltage-sensitive calcium channels, which triggers exocytosis of insulin-containing granules. In addition, glyburide also inhibits the SUR1-regulated nonselective cation (NC) Ca-ATP channel, melastatin 4 (transient receptor potential cation channel subfamily M member 4; (TRPM4)), thereby preventing capillary failure and brain swelling. SUR1-TRPM4 channels are formed by co-assembly of SUR1 with TRPM4 in neurons, astrocytes, and capillary endothelium during cerebral ischemia. Upon ischemia-induced ATP depletion, channels open which results in sodium influx, cytotoxic edema formation, capillary fragmentation and necrotic cell death. SUR1-TRPM4 is not expressed in normal, uninjured tissues.
An antidiabetic sulfonylurea derivative with actions like those of chlorpropamide
See also: Glyburide; Metformin Hydrochloride (component of).

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Drug Indication
Glyburide is indicated alone or as part of combination product with metformin, as an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus.
Amglidia is indicated for the treatment of neonatal diabetes mellitus, for use in newborns, infants and children. Sulphonylureas like Amglidia have been shown to be effective in patients with mutations in the genes coding for the β-cell ATP-sensitive potassium channel and chromosome 6q24-related transient neonatal diabetes mellitus.
Treatment of large hemispheric infarction
Treatment of neonatal diabetes mellitus

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Mechanism of Action
Glyburide belongs to a class of drugs known as sulfonylureas. These drugs act by closing ATP-sensitive potassium channels on pancreatic beta cells. The ATP-sensitive potassium channels on beta cells are known as sulfonylurea receptor 1 (SUR1). Under low glucose concentrations, SUR1 remains open, allowing for potassium ion efflux to create a -70mV membrane potential. Normally SUR1 closes in response to high glucose concentrations, the membrane potential of the cells becomes less negative, the cell depolarizes, voltage gated calcium channels open, calcium ions enter the cell, and the increased intracellular calcium concentration stimulates the release of insulin containing granules. Glyburide bypasses this process by forcing SUR1 closed and stimulating increased insulin secretion.

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Pharmacodynamics
Glyburide is a second generation sulfonylurea that stimulates insulin secretion through the closure of ATP-sensitive potassium channels on beta cells, raising intracellular potassium and calcium ion concentrations. Glibenclamide has a long duration of action as it is given once daily, and a wide therapeutic index as patients are started at doses as low as 0.75mg but that can increase as high as 10mg or more. Patients taking glyburide should be cautioned regarding an increased risk of cardiovascular mortality as seen with tolbutamide, another sulfonylurea.

C23H28CLN3O5S

494

493.143

C, 55.92; H, 5.71; Cl, 7.18; N, 8.51; O, 16.19; S, 6.49

10238-21-8

Glyburide-d3;1219803-02-7;Glyburide-d11;1189985-02-1; 52169-36-5 (potassium salt)

3488

White to off-white solid powder

1.4±0.1 g/cm3

705.7±70.0 °C at 760 mmHg

173-175°C

380.6±35.7 °C

0.0±2.4 mmHg at 25°C

1.623

5.19

121.98

3

5

8

33

746

0

ZNNLBTZKUZBEKO-UHFFFAOYSA-N

InChI=1S/C23H28ClN3O5S/c1-32-21-12-9-17(24)15-20(21)22(28)25-14-13-16-7-10-19(11-8-16)33(30,31)27-23(29)26-18-5-3-2-4-6-18/h7-12,15,18H,2-6,13-14H2,1H3,(H,25,28)(H2,26,27,29)

5-chloro-N-[2-[4-(cyclohexylcarbamoylsulfamoyl)phenyl]ethyl]-2-methoxybenzamide

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: ≥ 2.08 mg/mL (4.21 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 20.8 mg/mL澄清DMSO储备液加入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: ≥ 2.08 mg/mL (4.21 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 20.8 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；
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