Absorption, Distribution and Excretion
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/
For more Absorption, Distribution and Excretion (Complete) data for TOLAZAMIDE (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
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.

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Biological Half-Life
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/

Toxicity Summary
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.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Tolazamide is no longer marketed in the United Staes. Because no information is available on the use of tolazamide during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm 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.

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Interactions
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.

Tolazamide appears as white to off-white crystalline powder. Odorless or with a slight odor. (NTP, 1992)
Tolazamide is an N-sulfonylurea that is 1-tosylurea in which a hydrogen attached to the nitrogen at position 3 is replaced by an azepan-1-yl group. A hypoglycemic agent, it is used for the treatment of type 2 diabetes mellitus. It has a role as a hypoglycemic agent and a potassium channel blocker.
A sulphonylurea hypoglycemic agent with actions and uses similar to those of chlorpropamide.
Tolazamide is a Sulfonylurea.
Tolazamide is an intermediate-acting, first-generation sulfonylurea with hypoglycemic activity. Tolazamide is converted into five major metabolites that are excreted into the urine. Tolazamide is more potent than tolbutamide and similar in potency to chlorpropamide on a milligram basis. This agent may cause cholestatic jaundice.
A sulphonylurea hypoglycemic agent with actions and uses similar to those of chlorpropamide.
A sulphonylurea hypoglycemic agent with actions and uses similar to those of CHLORPROPAMIDE.

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Drug Indication
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.

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Mechanism of Action
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/

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Therapeutic Uses
Hypoglycemic Agents
...THIS POTENT AGENT LACKS ANTIDIURETIC ACTION & MAY BE ESPECIALLY USEFUL IN TREATMENT OF PT WHO HAVE TENDENCY TO RETAIN WATER.
SULFONYLUREAS SHOULD BE USED ONLY IN SUBJECTS WITH DIABETES OF MATURITY-ONSET TYPE WHO CANNOT BE TREATED WITH DIET ALONE OR WHO ARE UNWILLING OR UNABLE TO TAKE INSULIN IF WT REDN & DIETARY CONTROL FAIL. /SULFONYLUREAS/
ORAL HYPOGLYCEMIC
Sulfonylureas are indicated as adjunctive therapy to diet and exercise in the treatment and control of certain patients with NIDDM (Type II diabetes; previously known as adult onset diabetes, maturity onset diabetes, ketosis resistant diabetes, or stable diabetes), which occurs in individuals who produce or secrete insufficient quantities of endogenous insulin or who have developed resistance to endogenous insulin. An attempt to control diabetes through changes; in diet and level of physical activity is usually first line management before beginning pharmacologic treatment. Those patients not responding adequately to diet alone or those patients requiring diet plus insulin, especially if they require 40 USP Units or less of insulin a day, may be candidates for therapy with a sulfonylurea as monotherapy or combination therapy. /Included in US product labeling; Sulfonylurea antidiabetic agents/

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Drug Warnings
HEMATOLOGICAL (LEUKOPENIA, AGRANULOCYTOSIS, THROMBOCYTOPENIA, PANCYTOPENIA, & HEMOLYTIC ANEMIA), CUTANEOUS (RASHES, PHOTOSENSITIVITY), GI (NAUSEA, VOMITING, RARELY HEMORRHAGE), & HEPATIC (INCR SERUM ALKALINE PHOSPHATASE, CHOLESTATIC JAUNDICE) REACTIONS HAVE BEEN REPORTED.
...CONTRAINDICATED IN DIABETES COMPLICATED BY ACIDOSIS, KETOSIS, SEVERE INFECTIONS, COMA, SEVERE TRAUMA, OR MAJOR SURGERY.
MOST REACTIONS ARE OBSERVED IN PT OVER 50 YR OF AGE, & THEY ARE MORE LIKELY TO OCCUR IN PT WITH IMPAIRED HEPATIC OR RENAL FUNCTION. OVERDOSAGE OR INADEQUATE OR IRREGULAR FOOD INTAKE MAY INITIATE HYPOGLYCEMIA.
SULFONYLUREAS SHOULD NOT BE USED IN PT WITH HEPATIC OR RENAL INSUFFICIENCY BECAUSE OF IMPORTANT ROLE OF LIVER IN THEIR METABOLISM & OF KIDNEY IN EXCRETION OF DRUGS & THEIR METABOLITES. /SULFONYLUREAS/
For more Drug Warnings (Complete) data for TOLAZAMIDE (17 total), please visit the HSDB record page.

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Pharmacodynamics
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.

C14H21N3O3S

311.3998

311.13

1156-19-0

5503

Crystals
WHITE TO OFF-WHITE, CRYSTALLINE POWDER

1.29g/cm3

289 °C772 mm Hg(lit.)

171-173 °C(lit.)

100 °C

1.596

3.574

2

4

3

21

431

0

S(C1C([H])=C([H])C(C([H])([H])[H])=C([H])C=1[H])(N([H])C(N([H])N1C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H])=O)(=O)=O

OUDSBRTVNLOZBN-UHFFFAOYSA-N

InChI=1S/C14H21N3O3S/c1-12-6-8-13(9-7-12)21(19,20)16-14(18)15-17-10-4-2-3-5-11-17/h6-9H,2-5,10-11H2,1H3,(H2,15,16,18)

1-(azepan-1-yl)-3-(4-methylphenyl)sulfonylurea

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)

DMSO : ≥ 39 mg/mL (~125.24 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)