Tolbutamide

270.35

270.35

1984428

200-594-3

982XCM1FOI

757354|23813

DTXSID8021359

C66610

WHITE OR PRACTICALLY WHITE CRYSTALLINE POWDER|Crystals

A - Alimentary tract and metabolism|V - Various

2935009090

83.6

2.3

Tolbutamide appears as white crystals. (NTP, 1992)

1.245 g/cm³ @ Temp: 25 °C

128.5-129.5 °C

213.9±26.8 °C

1.557

soluble in chloroform.

Refrigerator

Oral-rat LD50: 2490 mg/kg; Oral-Mouse LD50: 490 mg/kg

Thermal decomposition emits toxic nitrogen oxides and sulfur oxide fumes

5.16None

5.16|pKa= 5.16

163 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]|161.9 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

PRACTICALLY ODORLESS; HAS SLIGHTLY BITTER TASTE /SODIUM SALT/

Insoluble in water.

Amides and Imides

TOLBUTAMIDE is an amide. Amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx). This chemical is incompatible with acids. (NTP, 1992).

NONH for all modes of transport

2

20/21/22-40-43-36-11

26-36/37/39-36/37-16-24/25

YS4550000

F,Xn

The warehouse is low-temperature, ventilated and dry; stored separately from food materials

Stable. Combustible.

P201, P202, P260, P261, P264, P270, P272, P280, P281, P301+P312, P302+P352, P307+P311, P308+P313, P321, P330, P333+P313, P363, P405, P501

H302

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

NTP TR No 031; Route: oral in feed; Species: rats and mice. NTIS No PB274483/AS.[NTP; Division of Toxicology Research and Testing; Management Status Report; 07/07/93; p.27]

Flash point data for this chemical are not available. It is probably combustible. (NTP, 1992)

|Danger|H302 (28.57%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P261, P264, P270, P272, P280, P281, P301+P312, P302+P352, P307+P311, P308+P313, P321, P330, P333+P313, P363, P405, and P501|Aggregated GHS information provided by 7 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

SMALL SPILLS AND LEAKAGE: If a spill of this chemical occurs, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with acetone and transfer the dampened material to a suitable container. Use absorbent paper dampened with acetone to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with acetone followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should store this material in a refrigerator. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

highly toxic

Oral, mouse: LD50 = 2600 mg/kg

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.

A bioassay of tolbutamide for possible carcinogenicity was conducted by admin the test material in the diet to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats of each sex were admin tolbutamide at one of two doses, either 12,000 or 24,000 ppm, 5 days/wk for 78 wk, then observed for an additional 28 wk. Matched control groups consisted of 15 untreated rats of each sex. All surviving rats were /sacrificed/ at 102-104 wk. Groups of 35 mice of each sex were admin tolbutamide at one of two doses, either 25,000 or 50,000 ppm, 5 days/wk for 78 wk, then observed for an additional 24-26 wk. Matched control groups consisted of 15 untreated mice of each sex. All surviving mice were /sacrificed/ at 102-104 wk. Mean body weights of the treated rats and mice were lower than those of the corresponding matched controls during the entire study; however, survival was not significantly affected by treatment in either species. In both sexes of both species, survival was considered to be adequate for meaningful statistical analyses of the incidence of tumors. In both the rats and mice, a variety of neoplasms were found in both the tolbutamide treated and control groups. None of the neoplasms were present in statistically significant incr incidence in treated groups of either species as compared with control groups and were not considered to be cmpd related. It is concluded that under the conditions of this bioassay, tolbutamide was not carcinogenic for either Fischer 344 rats or B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative.

Approximately 95% bound to plasma proteins.

For treatment of NIDDM (non-insulin-dependent diabetes mellitus) in conjunction with diet and exercise.

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.

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.

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.

Substances which lower blood glucose levels. (See all compounds classified as Hypoglycemic Agents.)

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/

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.

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/

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/

SYMPTOMS: Symptoms of exposure to this chemical may include aplastic anemia, hypoglycemia, nausea, vomiting, weakness, intolerance to alcohol, skin eruptions, and rarely, leukopenia, thrombocytopenia, thyroid suppression, hyperlipemia or gastrointestinal bleeding from ulcers. ACUTE/CHRONIC HAZARDS: When heated to decomposition this compound emits very toxic fumes. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. If symptoms (such as redness or irritation) develop, immediately transport the victim to a hospital. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

HYPOGLYCEMIA INDUCED BY EVEN HIGH DOSES OF TOLBUTAMIDE IS GENERALLY NOT AS SEVERE AS CAN BE INDUCED BY INSULIN, HENCE INCIDENCE OF ACUTE HYPOGLYCEMIC REACTIONS IS LOWER WITH TOLBUTAMIDE.|Coma or altered mental status is generally the most important presenting sign in the majority (90%) of patients who have ingested excessive doses of the sulfonylureas ... /Sulfonylurea/

Apo-Tolbutamide

Benzenesulfonamide, N-[(butylamino)carbonyl]-4-methyl-: ACTIVE

TYPE C PROCEDURE FOR PLASMA SAMPLES USING GAS CHROMATOGRAPH, FITTED WITH FLAME IONIZATION DETECTORS. TOLAZAMIDE & BARBITURATES ARE INTERFERING SUBSTANCES.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients