톨라자마이드

log Kow= 2.69

2.5

2.34

Crystals

WHITE TO OFF-WHITE, CRYSTALLINE POWDER

less than 1 mg/mL at 77 °F (NTP, 1992)

VERY SLIGHTLY SOL IN WATER; FREELY SOL IN CHLOROFORM; SOL IN ACETONE; SIGHTLY SOL IN ALCOHOL

In water, 65.4 mg/l @ 30 °C

3.08e-01 g/L

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

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

322 to 336 °F (with decomposition) (NTP, 1992)

170-173 °C

170-173 °C

170 - 173 °C

Tolazamide appears as white to off-white crystalline powder. Odorless or with a slight odor. (NTP, 1992)

Solid

175.4 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID3021358]

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

159.41 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

This chemical does not meet GHS hazard criteria for 50% (1 of 2) of reports.

Danger

H370 (50%): Causes damage to organs [Danger Specific target organ toxicity, single exposure]

P260, P264, P270, P308+P316, P321, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 2 reports by companies from 2 notifications to the ECHA C&L Inventory.

SYMPTOMS: Symptoms of exposure to this compound may include nausea, vomiting, epigastric pain, dizziness, weakness, paresthesia, sensitivity reactions such as fever, eosinophilia, jaundice and skin rashes, blood disorders such as leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis, and intolerance to alcohol (with facial flushing). Hypoglycemia can also occur. Hematological disorders include pancytopenia and hemolytic anemia. Photosensitivity, hemorrhage, increased serum alkaline phosphatase and cholestatic jaundice have been reported. Other symptoms may include heartburn, fatigue, malaise and allergic skin reactions which include pruritis, erythema, urticaria and morbilliform or maculopapular eruptions.

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).

TOLAZAMIDE 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. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

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)

DRUGS THAT MAY INCR RISK OF HYPOGLYCEMIA FROM SULFONYL UREAS INCL OTHER HYPOGLYCEMIC AGENTS, SULFONAMIDES, PROPRANOLOL, SALICYLATES, PHENYLBUTAZONE, PROBENECID, DICUMAROL, CHLORAMPHENICOL, MONOAMINE OXIDASE INHIBITORS, & ALCOHOL. /SULFONYLUREAS/

...TOLAZAMIDE...MAY INTERACT WITH GUANETHIDINE...

HYPOGLYCEMIC ACTIVITY OF CHLORPROPAMIDE MAY BE ENHANCED BY CONCURRENT ADMIN OF CLOFIBRATE. ... SULFONYLUREAS...TOLAZAMIDE...DEMONSTRATED SIMILAR INTERACTION WITH CLOFIBRATE. HALOFENATE...WAS REPORTED TO ENHANCE HYPOGLYCEMIC EFFECT OF SULFONYLUREAS TO GREATER DEGREE THAN CLOFIBRATE.

ISONIAZID MAY INCR BLOOD GLUCOSE LEVELS & IMPAIR GLUCOSE TOLERANCE. ... PRECAUTIONS ARE INDICATED WHEN ISONIAZID IS ADMIN TO DIABETIC PT TREATED BY...ORAL HYPOGLYCEMICS (EG, SULFONYLUREAS...).

For more Interactions (Complete) data for TOLAZAMIDE (25 total), please visit the HSDB record page.

Sulfonylureas likely bind to ATP-sensitive potassium-channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin.

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=1156-19-0]

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).

A - Alimentary tract and metabolism

QA - Alimentary tract and metabolism

Tolazamide is an oral blood glucose lowering drug of the sulfonylurea class. Tolazamide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which tolazamide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. Some patients who are initially responsive to oral hypoglycemic drugs, including tolazamide, may become unresponsive or poorly responsive over time. Alternatively, tolazamide may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs. In addition to its blood glucose lowering actions, tolazamide produces a mild diuresis by enhancement of renal free water clearance.

Sulfonylureas likely bind to ATP-sensitive potassium-channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin.

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/

Sulfonylureas lower blood glucose in 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 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. Insulin is a hormone that lowers blood glucose and controls the storage and metabolism of carbohydrates, proteins, and fats. Therefore, sulfonylureas are effective only in patients whose pancreata are capable of producing insulin. /Sulfonylurea antidiabetic agents/

The average biological half-life of the drug is 7 hours.

PLASMA T/2 IS ABOUT 7 HR...

AVG BIOLOGICAL HALF LIFE...IS 7 HR.

Half-life...7 /hours/ /from table/

Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0 to 70%.

TOLAZAMIDE IS METABOLIZED TO A NUMBER OF HYPOGLYCEMIC SUBSTANCES...

Sulfonylureas are rapidly absorbed from the gastrointestinal tract, transported in the blood in highly protein-bound complexes, and subjected to extensive hepatic metabolism (except for chlorpropamide). Wide variation exists among the sulfonylureas in hepatic metabolism and remnal clearance, factors that tend to alter the steady-state serum levels. Metabolites may be active, so there may be a variation between the plasma half-life of the parent drug and the degree of hypoglycemia encountered. /Sulfonylurea/

Active metabolites may accumulate in renal failure. /from table/

Although the exact metabolic fate of tolazamide has not been clearly established, the drug is metabolized, probably in the liver, to two hydroxymetabolites, p-toluenesulfonamide, p-carboxytolazamide, and an unidentified metabolite; several of these metabolites are pharmacologically active. Tolazamide is excreted in urine principally as metabolites; small amounts are excreted in urine unchanged.

Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0 to 70%. Route of Elimination: Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0% to 70%. They are excreted principally in the urine. Half Life: The average biological half-life of the drug is 7 hours.

9LT1BRO48Q

TOLAZAMIDE

Established Pharmacologic Class [EPC] - Sulfonylurea

Chemical Structure [CS] - Sulfonylurea Compounds

Tolazamide is a Sulfonylurea.

Rapidly and well absorbed from the gastrointestinal tract.

Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0% to 70%. They are excreted principally in the urine.

AFTER ORAL ADMIN PEAK PLASMA LEVELS REACH PEAK IN 4-8 HR.

TOLAZAMIDE IS SLOWLY ABSORBED; ONSET OF HYPOGLYCEMIC ACTION OCCURS @ 4-6 HR & PERSISTS @ SIGNIFICANT LEVEL UP TO 15 HR AFTER SINGLE DOSE. TOLAZAMIDE IS METABOLIZED TO NUMBER OF HYPOGLYCEMIC SUBSTANCES THAT ARE LARGELY EXCRETED BY KIDNEY.

Some metabolites with moderate activity excreted via kidney. /from table/

Excreted (percentage)...85-95 /from table/

Therap cat: Antidiabetic

An orally effective hypoglycemic drug.

For use as an adjunct to diet to lower the blood glucose in patients with non-insulin dependent diabetes mellitus (Type II) whose hyperglycemia cannot be satisfactorily controlled by diet alone.

Prepn: Wright, Willette, J Med Pharm Chem 5, 815 (1962); Wright, British patent 887,886 (1962 to Upjohn).

METHYL P-TOLYLSULFONYLCARBAMATE IS CAUSED TO UNDERGO AMMONOLYSIS TYPE OF REACTION WITH 1-AMINOHEXAMETHYLENEIMINE, US PATENT 3,063,903.