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Tolbutamide (also known as HLS 831; trade names: Artosin, Diabetol, Orinase), a sulfonylurea analog, is a potent and selective inhibitor of potassium channel used as an oral blood-glucose-lowering/hypoglycemic medication. It may be used for the treatment of type II diabetes.
Physicochemical Properties
| Molecular Formula | C12H18N2O3S |
| Molecular Weight | 270.35 |
| Exact Mass | 270.103 |
| Elemental Analysis | C, 53.31; H, 6.71; N, 10.36; O, 17.75; S, 11.86 |
| CAS # | 64-77-7 |
| Related CAS # | Tolbutamide-d9;1219794-57-6;Tolbutamide sodium;473-41-6;Tolbutamide-13C |
| PubChem CID | 5505 |
| Appearance | White to off-white solid powder |
| Density | 1.2±0.1 g/cm3 |
| Boiling Point | 430.0±38.0 °C at 760 mmHg |
| Melting Point | 128-130°C |
| Flash Point | 213.9±26.8 °C |
| Vapour Pressure | 0.0±1.1 mmHg at 25°C |
| Index of Refraction | 1.557 |
| LogP | 2.93 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 3 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 18 |
| Complexity | 354 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | JLRGJRBPOGGCBT-UHFFFAOYSA-N |
| InChi Code | 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) |
| Chemical Name | 1-butyl-3-(4-methylphenyl)sulfonylurea |
| Synonyms | olbutamide, Orinase; Arkozal; Willbutamide; Butamide; Diabetamid; Ipoglicone; trade names: Artosin, Diabetol, Orinase, HLS 831, HLS831, HLS-831 |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| Targets | K/potassium channel; CYP2C9 | ||
| ln Vitro |
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| ln Vivo |
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| Enzyme Assay | 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 | 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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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Readily absorbed following oral administration. Tolbutamide is detectable in plasma 30-60 minutes following oral administration of a single dose with peak plasma concentrations occurring within 3-5 hours. Absorption is unaltered if taken with food but is increased with high pH. Unchanged drug and metabolites are eliminated in the urine and feces. Approximately 75-85% of a single orally administered dose is excreted in the urine principally as the 1-butyl-3-p-carboxyphenylsulfonylurea within 24 hours. AFTER ORAL ADMIN, SULFONYLUREAS ARE RAPIDLY ABSORBED. /SULFONYLUREAS/ TOLBUTAMIDE CAN BE DETECTED IN BLOOD WITHIN 30 MIN AFTER ORAL ADMIN; PEAK CONCN ARE REACHED WITHIN 3 TO 5 HR. .../IT/ IS BOUND TO PLASMA PROTEINS. ... HALF-LIFE OF TOLBUTAMIDE IS ABOUT 5 HR. IN CONTRAST TO STUDIES REPORTED IN ANIMALS, METABOLIC CLEARANCE OF...TOLBUTAMIDE IN MAN HAS BEEN SHOWN TO BE UNALTERED BY FASTING. Excreted (percentage)...100 /from table/ Metabolism / Metabolites Metabolized in the liver principally via oxidation of the p-methyl group producing the carboxyl metabolite, 1-butyl-3-p-carboxyphenylsulfonylurea. May also be metabolized to hydroxytolbutamide. Tolbutamide does not undergo acetylation like antibacterial sulfonamides as it does not have a p-amino group. ...MAJOR TOLBUTAMIDE METAB IN MAN HAS BEEN IDENTIFIED AS 1-BUTYL-3-P-CARBOXYPHENYLSULFONYLUREA... 1-BUTYL-3-P-HYDROXYMETHYLPHENYLSULFONYLUREA IS ALSO FORMED IN SMALL AMT. IN RAT, MAJOR URINARY METAB, 1-BUTYL-3-P-HYDROXYMETHYLPHENYLSULFONYLUREA COMPRISED 75% OF DOSE, BUT SMALL AMT OF 1-BUTYL-3-P-CARBOXYPHENYLSULFONYLUREA & P-TOLYLSULFONYLUREA, COMPRISING 5% OF DOSE, WERE ALSO PRESENT. ALTHOUGH 1-BUTYL-3-P-HYDROXYMETHYLPHENYLSULFONYLUREA HAS BEEN REPORTED AS PRINCIPAL METAB IN CAT.../IT IS CLAIMED/ THAT CAT METABOLIZES TOLBUTAMIDE IN SAME WAY AS DOG. .../IT HAS BEEN SHOWN/ THAT TOLBUTAMIDE IS TRANSFORMED INTO 1-BUTYL-3-P-CARBOXYPHENYLSULFONYLUREA IN GUINEA PIGS & RABBITS. IN CONTRAST TO RATS, RABBITS & MAN, DOGS METABOLIZE TOLBUTAMIDE...INTO P-TOLYLSULFONYLUREA & P-TOLYLSULFONAMIDE BY MECHANISM INVOLVING HYDROLYSIS. For more Metabolism/Metabolites (Complete) data for TOLBUTAMIDE (7 total), please visit the HSDB record page. Tolbutamide has known human metabolites that include 4-Hydroxytolbutamide. Biological Half-Life Approximately 7 hours with interindividual variations ranging from 4-25 hours. Tolbutamide has the shortest duration of action, 6-12 hours, of the antidiabetic sulfonylureas. Half-life...3-25 /hours/ /from table/ |
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| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Tolbutamide is no longer marketed in the United States. It is excreted into breastmilk in small amounts that should cause no harm to the breastfed infant. 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 Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Approximately 95% bound to plasma proteins. Interactions SULFAPHENAZOLE ENHANCES ACTION OF TOLBUTAMIDE & MAY CAUSE SYMPTOMS OF SEVERE HYPOGLYCEMIA IN DIABETIC PT. IT IS UNCLEAR WHETHER THIS INTERACTION ALSO OCCURS WITH OTHER SULFONAMIDES OR SULFONYLUREA COMPD. HYPOGLYCEMIC ACTIVITY OF TOLBUTAMIDE MAY BE ENHANCED BY CONCURRENT ADMIN OF PHENYLBUTAZONE, & DOWNWARD ADJUSTMENT OF TOLBUTAMIDE DOSAGE MAY BE INDICATED. ... ALTHOUGH NOT DOCUMENTED, OXYPHENBUTAZONE & POSSIBLY SULFINPYRAZONE CAN BE EXPECTED TO INTERACT SIMILARLY TO PHENYLBUTAZONE. SINCE MAO INHIBITORS MAY ENHANCE HYPOGLYCEMIC ACTION OF INSULIN IN ANIMALS & IN HUMAN DIABETIC PT, CONCURRENT ADMIN OF MAO INHIBITORS & INSULIN TO DIABETIC SUBJECTS MAY BE POTENTIALLY DANGEROUS. .../TOLBUTAMIDE HAS/ BEEN REPORTED TO INTERACT WITH MAO INHIBITORS. DICUMAROL INCR SERUM HALF-LIFE OF TOLBUTAMIDE & MAY CAUSE SYMPTOMS OF HYPOGLYCEMIA. THIS EFFECT USUALLY OCCURS 3-4 DAYS AFTER INITIATING DICUMAROL THERAPY. ...PHENPROCOUMON INTERACTS WITH TOLBUTAMIDE IN ANIMALS. ...TOLBUTAMIDE DISPLACES WARFARIN FROM PROTEIN BINDING SITES IN VITRO. For more Interactions (Complete) data for TOLBUTAMIDE (10 total), please visit the HSDB record page. |
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| References |
[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. |
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| Additional Infomation |
Tolbutamide appears as white crystals. (NTP, 1992) Tolbutamide is an N-sulfonylurea that consists of 1-butylurea having a tosyl group attached at the 3-position. It has a role as a hypoglycemic agent, a potassium channel blocker, a human metabolite and an insulin secretagogue. Tolbutamide is an oral antihyperglycemic agent used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). It is structurally similar to acetohexamide, chlorpropamide and tolazamide and 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. Tolbutamide appears to be metabolized in the liver. Tolbutamide and its metabolites are excreted in urine (75-85%) and feces. Tolbutamide is a Sulfonylurea. Tolbutamide has been reported in Homo sapiens with data available. Tolbutamide is a short-acting, first-generation sulfonylurea with hypoglycemic activity. Compared to second-generation sulfonylureas, tolbutamide is more likely to cause adverse effects, such as jaundice. This agent is rapidly metabolized by CYPC29. A sulphonylurea hypoglycemic agent with actions and uses similar to those of CHLORPROPAMIDE. (From Martindale, The Extra Pharmacopoeia, 30th ed, p290) See also: Tolbutamide Sodium (has salt form). Drug Indication For treatment of NIDDM (non-insulin-dependent diabetes mellitus) in conjunction with diet and exercise. Mechanism of Action Sulfonylureas lower blood glucose in patients with NIDDM by directly stimulating the acute release of insulin from functioning beta cells of pancreatic islet tissue by an unknown process that involves a sulfonylurea receptor (receptor 1) on the beta cell. Sulfonylureas inhibit the ATP-potassium channels on the beta cell membrane and potassium efflux, which results in depolarization and calcium influx, calcium-calmodulin binding, kinase activation, and release of insulin-containing granules by exocytosis, an effect similar to that of glucose. SULFONYLUREAS STIMULATE ISLET TISSUE TO SECRETE INSULIN. ... SULFONYLUREAS CAUSE DEGRANULATION OF BETA CELLS, A PHENOMENON ASSOC WITH INCR RATE OF SECRETION OF INSULIN. /SULFONYLUREAS/ ALTHOUGH MOLECULAR MECHANISM...NOT UNDERSTOOD, SEVERAL PERTINENT OBSERVATIONS HAVE BEEN MADE. ...TOLBUTAMIDE IS RESTRICTED IN ITS ACTION TO EXTRACELLULAR SPACE & DOES NOT NEED TO ENTER BETA CELL. INVOKED RELEASE OF INSULIN IS IMMEDIATE & INTIMATELY RELATED TO ACTION OF GLUCOSE...MAY SENSITIZE CELL TO NORMAL SECRETAGOGUE. Sulfonylureas are now...thought to act by a number of different mechanisms. 1. ...produce a depolarization of the pancreatic islet beta cell membrane potassium ion permeability. This results in a release of preformed insulin into the circulation and occurs mostly in non-insulin dependent diabetics. 2. ...reduce basal glucose output from the liver... 3. increase insulin receptor binding... 4. ...increasing intracellular levels of AMP... 5. increase insulin secretion by suppressing the release of glucagon and somatostatin from alpha and delta pancreatic cells. /Sulfonylureas/ Therapeutic Uses Hypoglycemic Agents IT IS USEFUL IN TREATMENT OF SELECtED CASES OF DIABETES MELLITUS, NAMELY MILD UNCOMPLICATED, STABLE DIABETES OF ADULT ONSET & WHICH CANNOT BE CONTROLLED BY DIET ALONE. ... IN DIABETIC PT PEAK EFFECT IS REACHED IN 5 TO 8 HR. DURATION OF ACTION IS USUALLY LESS THAN 24 HR... THERE IS NO FIXED DOSAGE OF SULFONYLUREA TO BE USED IN DIABETES MELLITUS. TREATMENT IS GUIDED BY INDIVIDUAL PATIENT'S RESPONSE... /SULFONYLUREAS/ ...REPORTS HAVE APPEARED OF SUCCESSFUL TREATMENT OF REACTIVE HYPOGLYCEMIAS DUE TO A VARIETY OF CAUSES WITH SULFONYLUREAS. /SULFONYLUREAS/ VET: OCCASIONAL, AS AN ORAL HYPOGLYCEMIC AGENT FOR DOGS. Drug Warnings TOXIC EFFECTS OF TOLBUTAMIDE INCL GI UPSET, WEAKNESS, HEADACHE, TINNITUS, PARESTHESIAS, ALLERGIC REACTIONS (PRURITUS, ERYTHEMA MULTIFORME, MACULOPAPULAR RASH, ALL USUALLY TRANSIENT)...CHOLESTATIC JAUNDICE MAY OCCUR (RARELY)... RARE LEUKOPENIA, THROMBOCYTOPENIA, PANCYTOPENIA & AGRANULOCYTOSIS OCCUR. Despite this relative lack of teratogenicity, tolbutamide should be avoided in pregnancy since the drug will not provide good control in patients who cannot be controlled by diet alone. SULFONYLUREAS SHOULD NOT BE USED IN PT WITH HEPATIC OR RENAL INSUFFICIENCY BECAUSE OF IMPORTANT ROLE OF LIVER IN THEIR METAB & OF KIDNEY IN EXCRETION OF DRUG & THEIR METABOLITES. ... THESE AGENTS ARE ALSO NOT RECOMMENDED FOR USE IN PREGNANCY... /SULFONYLUREAS/ Maternal Medication Usually Compatible with Breast-Feeding: Tolbutamide: Possible jaundice. /from Table 6/ For more Drug Warnings (Complete) data for TOLBUTAMIDE (16 total), please visit the HSDB record page. Pharmacodynamics Tolbutamide, a first-generation sulfonylurea antidiabetic agent, is used with diet to lower blood glucose levels in patients with diabetes mellitus type II. Tolbutamide is twice as potent as the related second-generation agent glipizide. Tolbutamide lowers blood sugar by stimulating the pancreas to secrete insulin and helping the body use insulin efficiently. The pancreas must be able to produce insulin for this drug to work. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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. 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. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.6989 mL | 18.4945 mL | 36.9891 mL | |
| 5 mM | 0.7398 mL | 3.6989 mL | 7.3978 mL | |
| 10 mM | 0.3699 mL | 1.8495 mL | 3.6989 mL |