Tolbutamide Chemical Structure

Tolbutamide Chemical Structure
Molecular Weight: 270.35

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Quality Control & MSDS

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Product Description

Biological Activity

Description Tolbutamide is an inhibitor of potassium channel, used for type II diabetes.
Targets Potassium channel [3]
In vitro Tolbutamide belongs to a class of medications called sulfonylureas. Tolbutamide lowers blood sugar by causing the pancreas to produce insulin (a natural substance that is needed to break down sugar in the body) and helping the body use insulin efficiently. This medication will only help lower blood sugar in people whose bodies produce insulin naturally. Tolbutamide is not used to treat type 1 diabetes (condition in which the body does not produce insulin and, therefore, cannot control the amount of sugar in the blood) or diabetic ketoacidosis (a serious condition that may occur if high blood sugar is not treated). Tolbutamide inhibits both the basal and the cyclic AMP-stimulated protein kinase activities and the IC50 of Tolbutamide is 4 mM. Similar Tolbutamide concentrations are required for half maximal inhibition of in vitro lipolysis induced by hormones (norepinephrine and ACTH) or by dibutyryl cyclic AMP plus theophylline. Tolbutamide also inhibits both soluble and membrane-bound protein kinase from canine heart. The Tolbutamide inhibition of adipose tissue cyclic AMP-dependent protein kinase is one possible explanation for the antilipolytic effects of this drug. [1] Tolbutamide inhibits C6-glioma cell proliferation by increasing Cx43, which correlates with a reduction in pRb phosphorylation due to the up-regulation of the Cdk inhibitors p21 and p27. [2] Cytosolic nucelotides enhance the Tolbutamide sensitivity of the ATP-dependent K+ channel in mouse pancreatic B cells by their combined actions at inhibitory and stimulatory receptors. [3] Tolbutamide inhibits glucagon-induced phosphorylation of the bifunctional enzyme protein in a dose-dependent manner. By adding 2 mM Tolbutamide, reduces activity of 6PF-2-K and increased activity of Fru-2,6-P2ase in the presence of 10(-9) M glucagon are partially restored. The present results suggest the possibility that Tolbutamide modulates the activity of hepatic 6PF-2-K/Fru-2,6-P2ase through inhibiting a phosphorylation of the enzyme protein. [4]
In vivo 450 mg Tolbutamide/kg/day given for 7 days significantly increases the binding of insulin to isolated adipocytes. The binding curves reflect an increase in the number of receptor sites rather than in the affinity. The effect is associated with an enhanced response to insulin of the adipose tissue, since the fat cells obtained from animals treated with Tolbutamide convert significantly more glucose to lipids in the presence of insulin than those obtained from the control group. However, the augmentation of insulin binding sites is observed only at a large tolbutamide dosage, which reduces the pancreatic insulin content, the secretory response of the isolated pancreas, and the serum insulin levels. Smaller doses, sufficient to produce metabolic effects via a stimulation of insulin secretion, do not provide additional insulin binding sites. [5]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

cAMP kinase assay Diced epididymal fat pads from fed Wistar rats (175-225 gm) are obtained after decapitation and incubated at 37 °C for two hours in Krebs-bicarbonate buffer containing 1.27 mM CaCl2. When added, Tolbutamide is present only during the incubation. After incubation fat pads are rinsed and sonicated in cold Krebs-bicarbonate buffer. The aqueous supematants from centrifugation at 50,000 × g for 30 minutes at 4 °C contained 0.75 to 1.25 mg protein per mL and are assayed for cyclic AMP-stimulated protein kinase activity. The assay is performed in 0.2 mL with these additions, 10 μmoles sodium glycerofiosphate pH 7.0, 2 μmoles sodium fluoride, 0.4 μmoles theophylline, 0.1 μmoles ethylene glyool bis (β-aminoethyl ether)-N, N'-tetraaoetic acid, 3 μmoles magnesium chloride, 0.3 mg mixed histone, 2 nmoles (γ- 32P) ATP, 1 nmoles cyclic AMP when indicated, and 0.05 ml of supernatant.

Cell Assay: [2]

Cell lines C6 glioma cells
Concentrations 400 μM
Incubation Time 24 hours
Method C6 glioma cells are incubated in serum-free DMEM at 37 °C for at least 24 hours before each experiment. Tolbutamide (400 μM) is incubated for 24 hours in serum-free medium. Incubations are performed at 37 °C in an atmosphere of 95% air/5% CO2 with 90–95% humidity.

Animal Study: [5]

Animal Models Male albino Wistar rats (200-300 g)
Formulation Tolbutamide is given as powder and mixed with food.
Dosages 450 mg/kg
Administration Tolbutamide is administered orally for 7 days.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Wray HL, et al, Biochem Biophys Res Commun. 1973, 53(1), 291-294.

[2] Sanchez-Alvarez R, et al, Glia, 2006, 54(2), 125-134.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-12-20)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02211079 Completed Healthy Janssen Research & Development, LLC September 2014 Phase 1
NCT02211079 Completed Healthy Janssen Research & Development, LLC September 2014 Phase 1
NCT01525628 Completed Hepatitis C, Chronic Boehringer Ingelheim April 2012 Phase 1
NCT01525628 Completed Hepatitis C, Chronic Boehringer Ingelheim April 2012 Phase 1
NCT01218620 Active, not recruiting Adult Solid Neoplasm National Cancer Institute (NCI) September 2010 Phase 1

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Chemical Information

Download Tolbutamide SDF
Molecular Weight (MW) 270.35
Formula

C12H18N2O3S

CAS No. 64-77-7
Storage 3 years -20℃Powder
6 months-80℃in solvent (DMSO, water, etc.)
Synonyms
Chemical Name 1-butyl-3-tosylurea

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