N-[(부틸아미노)카보닐]-4-메틸벤젠설폰아마이드

log Kow= 2.34

2.2

2.62

1.245 at 77 °F (NTP, 1992) - Denser than water; will sink

1.245 g/cu cm @ 25 °C

WHITE OR PRACTICALLY WHITE CRYSTALLINE POWDER

Crystals

less than 1 mg/mL at 61 °F (NTP, 1992)

SOL IN ALC & CHLOROFORM; FREELY SOL IN WATER; VERY SLIGHTLY SOL IN ETHER /SODIUM SALT/

DISSOLVES READILY IN AQ NAOH TO FORM SODIUM DERIV

SOL IN ETHANOL, CHLOROFORM; FREELY IN DIMETHYL CARBONATE; INSOL IN WATER

Sol in ethanol, ethyl ether, and chloroform.

Breast Feeding; Lactation; Milk, Human; Hypoglycemic Agents; Sulfonylurea Compounds

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

262 to 264 °F (NTP, 1992)

128.5-129.5 °C

MP: 41-43 °C; when anhyd, mp range is 130-133 °C /Sodium salt tetrahydrate/

128.5 °C

Tolbutamide appears as white crystals. (NTP, 1992)

Solid

5.16

pKa= 5.16

165.0 Ų [M-H]- [CCS Type: DT; Buffer gas: N2; Ionization: ESI-; Dataset: TOXCAST; Source Identifier: DTXSID8021359]

161.9 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

163 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

171.79 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Danger

H302 (28.6%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P260, P261, P264, P270, P272, P280, P301+P317, P302+P352, P308+P316, P318, P321, P330, P333+P317, P362+P364, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 7 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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.

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).

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).

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.

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.

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.

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)

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.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=64-77-7]

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/

Tolbutamide

TR-031: Bioassay of Tolbutamide for Possible Carcinogenicity (CASRN 64-77-7) (1977 )

09/26/77

No Evidence

No Evidence

No Evidence

Drug Induced Liver Injury Rank (DILIrank 2.0)

Tolbutamide

Ambiguous-DILI-concern

2

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

CHRONIC ADMIN OF 30 MG/KG OR OVER TO NORMAL DOGS IS HEPATOTOXIC...

.../CHRONIC STUDY WAS PERFORMED/ WITH TOLBUTAMIDE IN DOG. MARKED REDN IN PLASMA LEVELS OF DRUG OCCURRED AFTER.../ADMIN/ 100 MG/KG FOR 12 DAYS. WHEN... INCR GRADUALLY TO 300 MG/KG OVER PERIOD OF 10 DAYS, PLASMA LEVELS INCR BUT DID NOT ACHIEVE INITIAL VALUES. AT THIS HIGH DOSAGE...SIDE EFFECTS OCCURRED & DOG DIED ON 23RD DAY.

EXPTL, LIFELONG ADMIN OF TOLBUTAMIDE TO RATS AT DOSAGE LEVELS 5 TO 40 TIMES THOSE EMPLOYED IN HUMAN...HAS CAUSED OPACIFICATION OF LENS & CORNEA, VASCULARIZATION OF CORNEA, & POSTERIOR SYNECHIAS, USUALLY OBSERVABLE AT 8 TO 24 MO.

Tolbutamide was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Tolbutamide was tested at doses of 0.10, 0.33, 1.0, 3.3, and 10 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Tolbutamide was negative in these tests and the highest ineffective dose tested in any S. typhimurium strain was 10 mg/plate.

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.

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).

V - Various

A - Alimentary tract and metabolism

QV - Various

QA - Alimentary tract and metabolism

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.

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/

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/

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.

982XCM1FOI

TOLBUTAMIDE

Established Pharmacologic Class [EPC] - Sulfonylurea

Chemical Structure [CS] - Sulfonylurea Compounds

Tolbutamide is a Sulfonylurea.

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/

Therap cat: Antidiabetic

Therap cat (Vet): Hypoglycemic agent

An orally effective hypoglycemic drug.

FROM BUTYL ISOCYANATE & 4-TOLUENESULFONAMIDE SODIUM...

British patent 808,071 and Aumuller, Herr, German patent 1,066,575 (both 1959 to Hoechst); Ruschig et al, US patent 2,968,158 (1961 to Upjohn).