| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
Tolbutamide sodium (also known as HLS 831; trade names: Artosin, Diabetol, Orinase) is a potent and selective inhibitor of potassium channel, which is originally used as an oral hypoglycemic medication. The drug may be used for the management of type II diabetes. Tolbutamide has been reported to inhibit both the basal and the cyclic AMP-stimulated protein kinase activities with an IC50 value of 4mM for cyclic AMP-dependent kinase activity. In addition, Tolbutamide has been revealed to inhibit both soluble and membrane-bound protein kinase from canine heart.
| Targets |
K/potassium channel; CYP2C9; antidiabetic
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|---|---|
| ln Vitro |
In vitro activity: 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. 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. 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.
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| ln 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.
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| Cell Assay |
In the present work, researchers show that tolbutamide and dbcAMP increase the synthesis of the tumor suppressor protein Cx43 and that they decrease the level of Ki-67, a protein expressed when cells are proliferating. These effects were accompanied by a reduction in the phosphorylation of pRb, mainly on Ser-795, a residue critical for the control of cell proliferation. The decrease in the phosphorylation of pRb is not likely to be mediated by a reduction in the levels of D-type cyclins, since instead of decreasing the expression of cyclins, D1 and D3 increased slightly after treatment with tolbutamide or dbcAMP. However, the Cdk inhibitors p21 and p27 were up-regulated after treatment with tolbutamide and dbcAMP, suggesting that they would be involved in the decrease in pRb phosphorylation. When Cx43 was silenced by siRNA, neither tolbutamide nor dbcAMP were able to up-regulate p21 and consequently to reduce glioma cell proliferation, as judged by Ki-67 expression. In conclusion, tolbutamide and dbcAMP inhibit 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].
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| Animal Protocol |
The functional state of beta cells may influence the rate of their destruction in Type 1 (insulin-dependent) diabetes mellitus. We examined the effect of diazoxide, which inhibits insulin secretion, or tolbutamide, which stimulates insulin secretion, upon the incidence of diabetes in the non-obese-diabetic (NOD) mouse. Female mice were treated from 3-30 weeks of age with diet containing diazoxide 250 mg.kg-1 or tolbutamide 125 mg.kg-1. The cumulative incidence of diabetes at 35 weeks was similar in the diazoxide (16 of 24) and control (18 of 24) groups, but reduced in the tolbutamide group (10 of 23, p < 0.04 vs control group). In a second experiment, treatment was started from 9 weeks of age, by which time insulitis is already present. The cumulative incidence of diabetes at 35 weeks was 16 of 24 in controls, 15 of 24 on diazoxide and 11 of 24 on tolbutamide (p = NS vs control). A third experiment compared the effect of treatment from 3 weeks with control diet or diet containing tolbutamide 125 mg.kg-1 or 500 mg.kg-1. Diabetes was reduced by tolbutamide treatment, with a cumulative incidence of 25 of 31 in controls, 18 of 30 on tolbutamide 125 mg.kg-1 (p < 0.04) and 14 of 32 on 500 mg.kg-1 (p < 0.002), although the difference between the two treatment groups failed to reach statistical significance. A fourth experiment showed that treatment from 3-12 weeks with diazoxide 1000 mg.kg-1 increased the extent of insulitis compared with controls and animals treated with tolbutamide 500 mg.kg-1.[3]
Pretreatment of pregnant BALB/c mice with several low doses of tolbutamide protected against the fetolethal effects of a high dose. Pregnant mice were given single ip injections of 400 mg/kg in saline on day 13; 100 mg/kg/day on days 10, 11, 12, and 13; or 100 mg/kg/day on days 10, 11, and 12 and 400 mg/kg on day 13. On day 16 the single-treatment group had a significantly higher resorption rate than any other group. Fetolethality was not related to hypoglycemia. The protective effect of pretreatment may have been due to induction of maternal microsomal enzymes.[4] |
| ADME/Pharmacokinetics |
Absorption
It is readily absorbed after oral administration. Tolbutamide is detectable in plasma within 30-60 minutes after a single oral dose, with peak plasma concentrations occurring within 3-5 hours. Consumption with food does not affect absorption, but a higher pH may increase absorption. Excretion The drug and its metabolites are primarily excreted in urine and feces. Approximately 75-85% of a single oral dose is excreted in urine within 24 hours primarily as 1-butyl-3-p-carboxyphenylsulfonamide. Sulfonylureas are rapidly absorbed after oral administration. /Sulfonylureas/ Tolbutamide is detectable in blood within 30 minutes after oral administration; peak plasma concentrations are reached within 3 to 5 hours. …It binds to plasma proteins. …The half-life of tolbutamide is approximately 5 hours. Contrary to animal studies, research indicates that fasting does not alter the metabolic clearance of tolbutamide in humans. Excretion rate (percentage)……100 Metabolism/Metabolites: Primarily metabolized in the liver, through the oxidation of the methyl group to produce the carboxyl metabolite 1-butyl-3-p-carboxyphenylsulfonylurea. It may also be metabolized to hydroxytoluenebutyrate. Because toluenebutyrate does not contain a para-amino group, it does not undergo acetylation like antibacterial sulfonamides. View More ...The main toluenesulfonamide metabolite in the human body has been identified as 1-butyl-3-p-carboxyphenylsulfonylurea... A small amount of 1-butyl-3-p-hydroxymethylphenylsulfonylurea is also produced. Biological half-life Approximately 7 hours, with individual variability of 4-25 hours. Tolbutamide has the shortest duration of action among sulfonylurea antidiabetic drugs, ranging from 6-12 hours. Half-life...3-25 hours/ |
| Toxicity/Toxicokinetics |
Use during pregnancy and lactation
◉ Overview of use during lactation Tolbutamide is discontinued in the United States. It is excreted in small amounts into breast milk and usually does not harm the nursing infant. The nursing infant should be monitored for signs of hypoglycemia, such as irritability, lethargy, feeding difficulties, seizures, cyanosis, apnea, or hypothermia. If there is any concern, monitoring of the nursing infant's blood glucose levels is recommended while the mother is using hypoglycemic agents. ◉ Effects on nursing infants As of the revision date, no relevant published information was found. ◉ Effects on lactation and breast milk As of the revision date, no relevant published information was found. Drug interactions Sulfafenazole can enhance the effects of tolbutamide and may cause severe hypoglycemia in diabetic patients. It is currently unknown whether this interaction also occurs with other sulfonamides or sulfonylureas. Concurrent use of phenbutazone may enhance the hypoglycemic activity of tolbutamide, therefore a dose reduction of tolbutamide may be necessary. …Although not documented in the literature, similar interactions between phenbutazone and sulfadiazine are expected. Because monoamine oxidase inhibitors may enhance the hypoglycemic effect of insulin in animals and human diabetic patients, concurrent use of monoamine oxidase inhibitors and insulin in diabetic patients may pose a potential risk. …Tolbutamide has been reported to interact with monoamine oxidase inhibitors. View MoreNational Toxicology Program Research Protein binding Approximately 95% binds to plasma proteins. |
| References |
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| Additional Infomation |
Tolbutamide sodium is the sodium salt form of tolbutamide, a short-acting first-generation sulfonylurea hypoglycemic agent. Compared to second-generation sulfonylureas, tolbutamide is more likely to cause adverse reactions, such as jaundice. This drug is primarily metabolized rapidly by CYP29.
See also: Tolbutamide (with active fraction). |
| Molecular Formula |
C12H17N2O3S-.NA+
|
|---|---|
| Molecular Weight |
292.32978
|
| Exact Mass |
270.104
|
| CAS # |
473-41-6
|
| Related CAS # |
Tolbutamide;64-77-7;Tolbutamide-d9;1219794-57-6
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| PubChem CID |
23690448
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.184g/cm3
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| Index of Refraction |
1.532
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| LogP |
3.459
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| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
4
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
19
|
| Complexity |
360
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
[Na+].CCCCNC([N-]S(C1C=CC(C)=CC=1)(=O)=O)=O
|
| InChi Key |
QKHDBRQBSNZFAK-UHFFFAOYSA-M
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| InChi Code |
InChI=1S/C12H18N2O3S.Na/c1-3-4-9-13-12(15)14-18(16,17)11-7-5-10(2)6-8-11;/h5-8H,3-4,9H2,1-2H3,(H2,13,14,15);/q;+1/p-1
|
| Chemical Name |
sodium;butylcarbamoyl-(4-methylphenyl)sulfonylazanide
|
| Synonyms |
TOLBUTAMIDE SODIUM; Tolbutamide sodium salt; 473-41-6; Sodium tolbutamide; Orinase Diagnostic; Sodium butamide; Sodium orinase; Tolbutamide sodium, sterile;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.4208 mL | 17.1040 mL | 34.2079 mL | |
| 5 mM | 0.6842 mL | 3.4208 mL | 6.8416 mL | |
| 10 mM | 0.3421 mL | 1.7104 mL | 3.4208 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05097716 | Completed Has Results |
Drug: Ritlecitinib Drug: Tolbutamide |
Healthy Volunteers | Pfizer | November 2, 2021 | Phase 1 |
| NCT01185548 | Terminated Has Results |
Drug: Tolbutamide Drug: Tasisulam |
Lymphoma Advanced Cancer |
Eli Lilly and Company | July 2010 | Phase 1 |
| NCT03291288 | Completed Has Results |
Drug: Tolbutamide Drug: Midazolam |
Drug Interaction Potential | Daiichi Sankyo | February 26, 2018 | Phase 1 |
| NCT03716427 | Completed | Drug: CT1812 Drug: tolbutamide |
Healthy Volunteers | Cognition Therapeutics | November 10, 2016 | Phase 1 |
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