K/potassium channel; CYP2C9

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

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.

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].

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]

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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]

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Tolbutamide is given as powder and mixed with food; 450 mg/kg; oral gavage

Male albino Wistar rats

Absorption, Distribution and Excretion
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 reached within 3-5 hours. Consumption with food does not affect absorption, but a higher pH may increase absorption.
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 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 (percentage)……100 /from table/

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Metabolism/Metabolites
Primarily metabolized in the liver, through the oxidation of the methyl group to the carboxyl metabolite 1-butyl-3-p-carboxyphenylsulfonylurea. It may also be metabolized to hydroxytoluenebutyrate. Toluenebutyrate does not undergo acetylation like antimicrobial sulfonamides because it does not contain a para-amino group.
……The major metabolite of toluenebutyrate in humans has been identified as 1-butyl-3-p-carboxyphenylsulfonylurea……A small amount of 1-butyl-3-p-hydroxymethylphenylsulfonylurea is also produced.
In rats, the major metabolite 1-butyl-3-p-hydroxymethylphenylsulfonylurea accounts for 75% of the administered dose in urine, but small amounts of 1-butyl-3-p-carboxyphenylsulfonylurea and p-toluenebutyrate are also present, accounting for 5% of the administered dose.
While it has been reported that 1-butyl-3-p-hydroxymethylphenylsulfonylurea is the main metabolite in cats…/allegedly/ cats metabolize tolbutamide in the same way as dogs. Studies have shown that tolbutamide is converted to 1-butyl-3-p-carboxyphenylsulfonylurea in guinea pigs and rabbits.
Unlike rats, rabbits, and humans, dogs metabolize tolbutamide to p-toluenesulfonamide and p-toluenesulfonamide via hydrolysis.
For more complete data on the metabolism/metabolites of tolbutamide (7 metabolites in total), please visit the HSDB record page.
The known metabolite of tolbutamide in humans includes 4-hydroxytolbutamide.
Biological half-life
Approximately 7 hours, with individual variability of 4-25 hours.Of all sulfonylurea hypoglycemic agents, tolbutamide has the shortest duration of action, only 6-12 hours.
Half-life...3-25 hours/(Data from table)

Effects During Pregnancy and Lactation
◉ Summary of Use During Lactation
Tolbutamide is no longer marketed 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 closely monitored for signs of hypoglycemia, such as irritability, lethargy, feeding difficulties, seizures, cyanosis, apnea, or hypothermia. If in doubt, it is recommended to monitor the breastfed infant's blood glucose levels while the mother is receiving hypoglycemic medication. ◉ 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. Protein Binding Approximately 95% binds to plasma proteins. Interactions Sulfamethoxazole can enhance the effects of tolbutamide and may cause severe hypoglycemia in diabetic patients. It is unclear whether this interaction also occurs with other sulfonamides or sulfonylureas. Concomitant use of phenbutazone may enhance the hypoglycemic activity of tolbutamide, thus potentially requiring a dose reduction. Although not documented in the literature, similar interactions with phenbutazone and sulfadiazine are expected. Since monoamine oxidase inhibitors may enhance the hypoglycemic effect of insulin in animals and human diabetic patients, the concomitant use of monoamine oxidase inhibitors and insulin in diabetic patients may pose a potential danger. …Tolbutamide has been reported to interact with monoamine oxidase inhibitors. Dicoumarol can prolong the serum half-life of tolbutamide and may cause hypoglycemia. This effect typically appears 3–4 days after initiation of dicoumarol treatment. …Phenylacetocoumarol interacts with tolbutamide in animals. …Tolbutamide can displace warfarin from its protein binding site in vitro. For more complete data on tolbutamide interactions (10 in total), please visit the HSDB records page.

[1]. Biochem Biophys Res Commun.1973 Jul 2;53(1):291-4;
[2]. Glia.2006 Aug 1;54(2):125-34.
[3]. Diabetologia, 1993, 36: 487-492.
[4]. Teratology, 1976, 13(1): 65-70.

Tolbutamide is a white crystalline solid. (NTP, 1992)
Tolbutamide is an N-sulfonamide drug, composed of 1-butylurea with a tosylate group linked at the 3-position. It has hypoglycemic, potassium channel blocking, metabolic, and insulin secretion-stimulating effects.
Tolbutamide is an oral hypoglycemic agent used to treat non-insulin-dependent diabetes mellitus (NIDDM). Its structure is similar to acesulfame potassium, chlorpropamide, and tolbutamide, belonging to the sulfonylurea class of insulin secretagogues. Its mechanism of action is through stimulating the release of insulin from pancreatic β-cells. Sulfonylureas can increase basal and postprandial insulin secretion. These drugs differ in dosage, absorption rate, duration of action, elimination pathway, and binding sites targeting pancreatic β-cell receptors. Sulfonylureas can increase peripheral glucose utilization, reduce hepatic gluconeogenesis, and may increase the number and sensitivity of insulin receptors. Sulfonylureas are associated with weight gain, but to a lesser extent than insulin. Due to their mechanism of action, sulfonylureas can cause hypoglycemia, thus requiring continuous food intake to reduce this risk. The risk of hypoglycemia is higher in the elderly, the frail, and those who are malnourished. Tolbutamide appears to be metabolized in the liver. Tolbutamide and its metabolites are primarily excreted in urine (75-85%) and feces.
Tolbutamide is a sulfonylurea drug.
There are reports on the use of tolbutamide in humans, and relevant data are available.
Tolbutamide is a short-acting, first-generation sulfonylurea drug with hypoglycemic effects. Compared to second-generation sulfonylureas, tolbutamide is more likely to cause adverse reactions, such as jaundice. This drug is rapidly metabolized by CYP29.
A sulfonylurea hypoglycemic drug with similar effects and uses to chloropropamide. (Excerpt from Martindale Pharmacopoeia, 30th edition, p. 290)
See also: Tolbutamide sodium (in salt form). Indications Sulfonylureas are used to treat non-insulin-dependent diabetes mellitus (NIDDM) and require a combination of diet and exercise. Mechanism of Action Sulfonylureas lower blood glucose in NIDDM patients by directly stimulating pancreatic β-cells to release insulin through an unknown mechanism. This mechanism involves sulfonylurea receptors (receptor 1) on β-cells. Sulfonylureas inhibit ATP-potassium channels and potassium ion efflux on the β-cell membrane, leading to β-cell depolarization and calcium ion influx, calcium-calmodulin binding, kinase activation, and the release of insulin-containing granules via exocytosis, similar to the action of glucose. Sulfonylureas stimulate insulin secretion from pancreatic islet tissue. …Sulfonylureas cause β-cell degranulation, a phenomenon associated with an increased rate of insulin secretion. /Sulfonylureas/ Although the molecular mechanism is not fully elucidated, some relevant observations have been made. …The action of tolbutamide is confined to the extracellular space and does not require entry into β-cells. Induction of insulin release is immediate and closely related to the action of glucose…potentially making cells more sensitive to normal secretagogues.
Sulfonylureas are currently believed to act through several different mechanisms. 1. …leading to depolarization of potassium permeability in pancreatic β-cell membranes. This results in the release of pre-synthesized insulin into the bloodstream, primarily occurring in patients with non-insulin-dependent diabetes mellitus. 2. …reducing basal hepatic glucose output… 3. Increasing insulin receptor binding… 4. …increasing intracellular AMP levels… 5. Increasing insulin secretion by inhibiting the release of glucagon and somatostatin from pancreatic α-cells and δ-cells. /Sulfonylureas/

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Therapeutic Uses
Hydroxyglycemic Agents
Sulfonylureas can be used to treat certain cases of diabetes, namely mild, uncomplicated, stable diabetes in adults that cannot be controlled by diet alone. …In diabetic patients, the drugs reach peak efficacy within 5 to 8 hours. The duration of action is usually less than 24 hours…
There is no fixed dosage for sulfonylureas in the treatment of diabetes. Treatment regimens depend on individual patient response…/Sulfonylureas/
…Sulfonylureas have been reported to successfully treat reactive hypoglycemia from various causes. Sulfonylureas
Veterinary use: Occasionally used as an oral hypoglycemic agent in dogs.

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Drug Warnings
Tolbutamide toxicity includes gastrointestinal upset, weakness, headache, tinnitus, paresthesia, allergic reactions (pruritus, erythema multiforme, maculopapular rash, usually transient)…Cholestatic jaundice may occur (rare)…Rare leukopenia, thrombocytopenia, pancytopenia, and agranulocytosis.
Although tolbutamide has relatively low teratogenicity, it should be avoided in pregnant women because the drug is not effectively controlled by diet. Use alone.
Sulfonylureas should not be used in patients with hepatic or renal insufficiency, as the liver plays a crucial role in its metabolism and the kidneys play a crucial role in the excretion of the drug and its metabolites. ...These medications are also not recommended for use during pregnancy... /Sulfonylureas/
Maternal medications generally compatible with breastfeeding: Tolbutamide: May cause jaundice. /Excerpt from Table 6/
For more complete data on drug warnings for tolbutamide (16 in total), please visit the HSDB records page.

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Pharmacodynamics
Tolbutamide is a first-generation sulfonylurea hypoglycemic agent used in combination with diet therapy to lower blood sugar levels in patients with type 2 diabetes. Tolbutamide is twice as potent as glipizide, a second-generation drug in the same class. Tolbutamide lowers blood sugar by stimulating the pancreas to secrete insulin and helping the body use insulin effectively. The pancreas must be able to produce insulin for the drug to work.

C12H18N2O3S

270.35

270.103

C, 53.31; H, 6.71; N, 10.36; O, 17.75; S, 11.86

64-77-7

Tolbutamide-d9;1219794-57-6;Tolbutamide sodium;473-41-6;Tolbutamide-13C

5505

White to off-white solid powder

1.2±0.1 g/cm3

430.0±38.0 °C at 760 mmHg

128-130°C

213.9±26.8 °C

0.0±1.1 mmHg at 25°C

1.557

2.93

2

3

5

18

354

0

JLRGJRBPOGGCBT-UHFFFAOYSA-N

InChI=1S/C12H18N2O3S/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)

1-butyl-3-(4-methylphenyl)sulfonylurea

olbutamide, Orinase; Arkozal; Willbutamide; Butamide; Diabetamid; Ipoglicone; trade names: Artosin, Diabetol, Orinase, HLS 831, HLS831, HLS-831

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: ≥ 2.08 mg/mL (7.69 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 20.8 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: ≥ 2.08 mg/mL (7.69 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 20.8 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: ≥ 2.08 mg/mL (7.69 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 20.8 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.)