TOLAZAMIDE

US Previously Marketed

First approved in 1966

Details

Stereochemistry	ACHIRAL
Molecular Formula	C14H21N3O3S
Molecular Weight	311.4
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=CC=C(C=C1)S(=O)(=O)NC(=O)NN2CCCCCC2

InChI

InChIKey=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)

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB00839
Curator's Comment: Description was created based on several sources, including https://www.drugs.com/pro/tolinase.html

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. Tolazamide is used 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.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Sulfonylurea receptor 1, Kir6.2 13 Target ID: CHEMBL2096972 Sources: http://www.genome.jp/dbget-bin/www_bget?D00379	Agonist 2678		5.861 nM [Ki]
ATP-sensitive inward rectifier potassium channel 1 7 Target ID: CHEMBL1293292 Sources: http://www.drugbank.ca/drugs/DB00839	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Type 2 diabetes mellitus 259 Sources: https://www.drugs.com/pro/tolinase.html	Primary		Approved 8429	Tolazamide Approved Use Indicated as an adjunct to diet to lower the blood glucose in patients with noninsulin dependent diabetes mellitus (Type II) whose hyperglycemia cannot be satisfactorily controlled by diet alone. Launch Date 1984

C_max

Value	Dose	Co-administered	Analyte	Population
21.8 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7175719/	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:		TOLAZAMIDE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
260 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7175719/	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:		TOLAZAMIDE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
4.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7175719/	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:		TOLAZAMIDE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

Doses

Dose	Population	Adverse events
0.5 g 2 times / day multiple, oral Recommended Dose: 0.5 g, 2 times / day Route: oral Route: multiple Dose: 0.5 g, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/3041937/	unhealthy, 50 n = 8 Health Status: unhealthy Condition: diabetes mellitus Age Group: 50 Sex: M+F Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/3041937/	Sources: https://pubmed.ncbi.nlm.nih.gov/3041937/
0.75 g 1 times / day single, oral Overdose Dose: 0.75 g, 1 times / day Route: oral Route: single Dose: 0.75 g, 1 times / day Sources: https://link.springer.com/article/10.2165/00128415-200711730-00075	unhealthy, 59 n = 1 Health Status: unhealthy Condition: diabetes mellitus Age Group: 59 Sex: F Population Size: 1 Sources: https://link.springer.com/article/10.2165/00128415-200711730-00075	Other AEs: Shakiness... Other AEs: Shakiness Sources: https://link.springer.com/article/10.2165/00128415-200711730-00075
1 g 1 times / day single, oral Overdose Dose: 1 g, 1 times / day Route: oral Route: single Dose: 1 g, 1 times / day Sources: https://link.springer.com/article/10.2165/00128415-200711730-00075	unhealthy, 62 n = 1 Health Status: unhealthy Condition: diabetes mellitus Age Group: 62 Sex: F Population Size: 1 Sources: https://link.springer.com/article/10.2165/00128415-200711730-00075	Other AEs: Dizziness... Other AEs: Dizziness Sources: https://link.springer.com/article/10.2165/00128415-200711730-00075
0.5 g 1 times / day single, oral Overdose Dose: 0.5 g, 1 times / day Route: oral Route: single Dose: 0.5 g, 1 times / day Sources: https://link.springer.com/article/10.2165/00128415-200711730-00075	unhealthy, 69 n = 1 Health Status: unhealthy Condition: diabetes mellitus Age Group: 69 Sex: F Population Size: 1 Sources: https://link.springer.com/article/10.2165/00128415-200711730-00075	Other AEs: Dizziness... Other AEs: Dizziness Sources: https://link.springer.com/article/10.2165/00128415-200711730-00075

AEs

AE	Dose	Population
Shakiness	0.75 g 1 times / day single, oral Overdose Dose: 0.75 g, 1 times / day Route: oral Route: single Dose: 0.75 g, 1 times / day Sources: https://link.springer.com/article/10.2165/00128415-200711730-00075	unhealthy, 59 n = 1 Health Status: unhealthy Condition: diabetes mellitus Age Group: 59 Sex: F Population Size: 1 Sources: https://link.springer.com/article/10.2165/00128415-200711730-00075
Dizziness	1 g 1 times / day single, oral Overdose Dose: 1 g, 1 times / day Route: oral Route: single Dose: 1 g, 1 times / day Sources: https://link.springer.com/article/10.2165/00128415-200711730-00075	unhealthy, 62 n = 1 Health Status: unhealthy Condition: diabetes mellitus Age Group: 62 Sex: F Population Size: 1 Sources: https://link.springer.com/article/10.2165/00128415-200711730-00075
Dizziness	0.5 g 1 times / day single, oral Overdose Dose: 0.5 g, 1 times / day Route: oral Route: single Dose: 0.5 g, 1 times / day Sources: https://link.springer.com/article/10.2165/00128415-200711730-00075	unhealthy, 69 n = 1 Health Status: unhealthy Condition: diabetes mellitus Age Group: 69 Sex: F Population Size: 1 Sources: https://link.springer.com/article/10.2165/00128415-200711730-00075

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	substrate 1037

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
		GLUT1 9

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
GLUT1 15	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/2661591/	yes

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2C9 1037	substrate 3367 Sources: https://go.drugbank.com/drugs/DB00839, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821002/pdf/10.1177_2042018816638050.pdf	major
CYP3A4 1737	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821002/pdf/10.1177_2042018816638050.pdf	minor

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:9613	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:9613
ChemicalBook	CB9355686	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB9355686
MolPort	MolPort-001-826-273	https://www.molport.com/shop/molecule-link/MolPort-001-826-273
ZINC	ZINC000000057512	http://zinc15.docking.org/substances/ZINC000000057512
eMolecules	563632	https://www.emolecules.com/cgi-bin/more?vid=563632

PubMed

Title	Date	PubMed
Reduction of the severity of nephropathy in aging Fischer 344 rats treated with analogs of arylsulfonyluria.	1979 Jul	473209
Tolazamide-induced cholestasis.	1980 Aug	7403921
Potentiation of insulin action by a sulfonylurea in primary cultures of hepatocytes from normal and diabetic rats.	1983 Mar	6337899
Wernicke's encephalopathy induced by tolazamide.	1983 Sep 8	6410237
A case of chronic liver disease due to tolazamide.	1985 Jul	4007403
Transketolase abnormality in tolazamide-induced Wernicke's encephalopathy.	1986 Nov	3762968
Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor.	1995 Nov 17	7502040
[A 50-year history of new drugs in Japan-the development and progress of anti-diabetic drugs and the epidemiological aspects of diabetes mellitus].	2003	14570054
Selection of drugs to test the specificity of the Tg.AC assay by screening for induction of the gadd153 promoter in vitro.	2003 Aug	12730611
Barriers to self-monitoring of blood glucose among adults with diabetes in an HMO: a cross sectional study.	2003 Mar 19	12659642
Detection of anti-diabetics in equine plasma and urine by liquid chromatography-tandem mass spectrometry.	2004 Nov 5	15458724
Cardiovascular risk factors associated with insulin resistance: effects of oral antidiabetic agents.	2005	15901207
Prediction of pharmacological and xenobiotic responses to drugs based on time course gene expression profiles.	2009 Dec 2	19956587
Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database.	2009 Dec 3	19959591
A review of exenatide as adjunctive therapy in patients with type 2 diabetes.	2009 Sep 21	19920937
Glucose biosensors: an overview of use in clinical practice.	2010	22399892
Epac2: a sulfonylurea receptor?	2012 Feb	22260657

Patents

Sample Use Guides

In Vivo Use Guide

The usual starting dose of Tolinase Tablets (Tolazamide) for the mild to moderately severe Type II diabetic patient is 100–250 mg daily administered with breakfast or the first main meal. Generally, if the fasting blood glucose is less than 200 mg/dl, the starting dose is 100 mg/day as a single daily dose. If the fasting blood glucose value is greater than 200 mg/dl, the starting dose is 250 mg/day as a single dose. If the patient is malnourished, underweight, elderly, or not eating properly, the initial therapy should be 100 mg once a day.

Route of Administration: Oral

In Vitro Use Guide

Tolazamide (1 mM) block contractions induced by prostaglandin F2alpha and the thromboxane A2 mimetic U-46619 in rat aorta

Name

Type

Language

TOLAZAMIDE

Official Name

English

TOLAZAMIDE [USAN]

Common Name

English

TOLAZAMIDE [USP-RS]

Common Name

English

BENZENESULFONAMIDE, N-(((HEXAHYDRO-1H-AZEPIN-1-YL)AMINO)CARBONYL)-4-METHYL-

Systematic Name

English

TOLAZAMIDE [HSDB]

Common Name

English

TOLAZAMIDE [MART.]

Common Name

English

TOLAZAMIDE [MI]

Common Name

English

Tolazamide [WHO-DD]

Common Name

English

tolazamide [INN]

Common Name

English

TOLAZAMIDE [JAN]

Common Name

English

TOLBUTAMIDE IMPURITY C [EP IMPURITY]

Common Name

English

TOLAZAMIDE [VANDF]

Common Name

English

U-17835

Code

English

TOLAZAMIDE [ORANGE BOOK]

Common Name

English

1-(HEXAHYDRO-1H-AZEPIN-1-YL)-3-(P-TOLYLSULFONYL)UREA

Common Name

English

TOLAZAMIDE [USP MONOGRAPH]

Common Name

English

TOLINASE

Brand Name

English

NSC-70762

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C97936