Identification

Name
Tolazamide
Accession Number
DB00839  (APRD01267)
Type
Small Molecule
Groups
Approved, Investigational
Description

A sulphonylurea hypoglycemic agent with actions and uses similar to those of chlorpropamide.

Structure
Thumb
Synonyms
  • 1-(Hexahydro-1-azepinyl)-3-p-tolylsulfonylurea
  • 1-(Hexahydro-1H-azepin-1-yl)-3-(p-tolylsulfonyl)urea
  • 4-(p-Tolylsulfonyl)-1,1-hexamethylenesemicarbazide
  • N-(p-Toluenesulfonyl)-N'-hexamethyleniminourea
  • Tolazamid
  • Tolazamida
  • Tolazamide
  • Tolazamidum
External IDs
AI3-50826 / BRN 1323565 / CCRIS 591 / EINECS 214-588-3 / HSDB 3192 / NCI-C03327 / NSC-70762 / U 17835 / U-17835
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TolazamideTablet250 mg/1OralAmerincan Health Packaging2012-02-132015-05-31Us
TolazamideTablet250 mg/1OralPhysicians Total Care, Inc.1995-02-022012-06-30Us
TolazamideTablet500 mg/1OralMylan Pharmaceuticals2013-01-18Not applicableUs
TolazamideTablet250 mg/1OralPd Rx Pharmaceuticals, Inc.2010-01-05Not applicableUs
TolazamideTablet250 mg/1OralMylan Pharmaceuticals2013-01-18Not applicableUs
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
TolazamideTolazamide (100 mg/1)TabletOralMutual Pharmaceutical Company, Inc2006-12-28Not applicableUs
TolazamideTolazamide (500 mg/1)TabletOralMutual Pharmaceutical Company, Inc2006-12-28Not applicableUs
TolazamideTolazamide (250 mg/1)TabletOralMutual Pharmaceutical Company, Inc2006-12-28Not applicableUs
TolinaseTolazamide (100 mg/1)TabletOralUNSPECIFIED2006-04-11Not applicableUs
TolinaseTolazamide (500 mg/1)TabletOralUNSPECIFIED2006-04-11Not applicableUs
TolinaseTolazamide (250 mg/1)TabletOralUNSPECIFIED2006-04-11Not applicableUs
International/Other Brands
Desumide (Hua Shin) / Diabewas / Esulin (Chung Mei) / Norglycin (Pfizer) / Tolanase (Upjohn) / Tolinase
Categories
UNII
9LT1BRO48Q
CAS number
1156-19-0
Weight
Average: 311.4
Monoisotopic: 311.130362243
Chemical Formula
C14H21N3O3S
InChI Key
OUDSBRTVNLOZBN-UHFFFAOYSA-N
InChI
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)
IUPAC Name
1-(azepan-1-yl)-3-(4-methylbenzenesulfonyl)urea
SMILES
CC1=CC=C(C=C1)S(=O)(=O)NC(=O)NN1CCCCCC1

Pharmacology

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.

Associated Conditions
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.

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.

TargetActionsOrganism
ASulfonylurea receptor 1, Kir6.2
blocker
Human
Absorption

Rapidly and well absorbed from the gastrointestinal tract.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

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.

Clearance
Not Available
Toxicity

Overdosage of sulfonylureas can produce hypoglycemia. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(1S,6R)-3-{[3-(TRIFLUOROMETHYL)-5,6-DIHYDRO[1,2,4]TRIAZOLO[4,3-A]PYRAZIN-7(8H)-YL]CARBONYL}-6-(2,4,5-TRIFLUOROPHENYL)CYCLOHEX-3-EN-1-AMINE(1S,6R)-3-{[3-(TRIFLUOROMETHYL)-5,6-DIHYDRO[1,2,4]TRIAZOLO[4,3-A]PYRAZIN-7(8H)-YL]CARBONYL}-6-(2,4,5-TRIFLUOROPHENYL)CYCLOHEX-3-EN-1-AMINE may increase the hypoglycemic activities of Tolazamide.
2,4-thiazolidinedione2,4-thiazolidinedione may increase the hypoglycemic activities of Tolazamide.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypoglycemic activities of Tolazamide.
AcarboseAcarbose may increase the hypoglycemic activities of Tolazamide.
AcebutololAcebutolol may increase the hypoglycemic activities of Tolazamide.
AcenocoumarolTolazamide may increase the anticoagulant activities of Acenocoumarol.
AcetaminophenAcetaminophen may decrease the excretion rate of Tolazamide which could result in a higher serum level.
AcetohexamideAcetohexamide may increase the hypoglycemic activities of Tolazamide.
Acetylsalicylic acidAcetylsalicylic acid may increase the hypoglycemic activities of Tolazamide.
AICA ribonucleotideAICA ribonucleotide may increase the hypoglycemic activities of Tolazamide.
Food Interactions
Not Available

References

General References
  1. Tal A: Oral hypoglycemic agents in the treatment of type II diabetes. Am Fam Physician. 1993 Nov 1;48(6):1089-95. [PubMed:8237731]
  2. Granberry MC, Fonseca VA: Cardiovascular risk factors associated with insulin resistance: effects of oral antidiabetic agents. Am J Cardiovasc Drugs. 2005;5(3):201-9. [PubMed:15901207]
External Links
Human Metabolome Database
HMDB0014977
KEGG Drug
D00379
PubChem Compound
5503
PubChem Substance
46505642
ChemSpider
5302
ChEBI
9613
ChEMBL
CHEMBL817
Therapeutic Targets Database
DAP000919
PharmGKB
PA164774902
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Tolazamide
ATC Codes
A10BB05 — Tolazamide

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentImpaired Glucose Tolerance (IGT) / Type 2 Diabetes Mellitus1
Not AvailableCompletedNot AvailableType 2 Diabetes Mellitus3

Pharmacoeconomics

Manufacturers
  • Barr laboratories inc
  • Duramed pharmaceuticals inc sub barr laboratories inc
  • Interpharm inc
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Mutual pharmaceutical co inc
  • Mylan pharmaceuticals inc
  • Par pharmaceutical inc
  • Sandoz inc
  • Superpharm corp
  • Usl pharma inc
  • Watson laboratories inc
  • Pharmacia and upjohn co
Packagers
  • Apotheca Inc.
  • Central Texas Community Health Centers
  • Dispensing Solutions
  • Ivax Pharmaceuticals
  • Kaiser Foundation Hospital
  • Major Pharmaceuticals
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mutual Pharmaceutical Co.
  • Mylan
  • PCA LLC
  • PD-Rx Pharmaceuticals Inc.
  • Pharmaceutical Utilization Management Program VA Inc.
  • Pharmedix
  • Physicians Total Care Inc.
Dosage forms
FormRouteStrength
TabletOral100 mg/1
TabletOral250 mg/1
TabletOral500 mg/1
Prices
Unit descriptionCostUnit
Tolazamide 500 mg tablet1.41USD tablet
Tolinase 250 mg tablet1.23USD tablet
Tolazamide 250 mg tablet0.79USD tablet
Tolazamide 100 mg tablet0.41USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)170-173 °CPhysProp
water solubility65.4 mg/L (at 30 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP2.69SANGSTER (1993)
logS-3.68ADME Research, USCD
Predicted Properties
PropertyValueSource
Water Solubility0.308 mg/mLALOGPS
logP1.4ALOGPS
logP1.91ChemAxon
logS-3ALOGPS
pKa (Strongest Acidic)4.07ChemAxon
pKa (Strongest Basic)1.61ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area78.51 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity81.34 m3·mol-1ChemAxon
Polarizability32.82 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9749
Blood Brain Barrier+0.8467
Caco-2 permeable-0.6444
P-glycoprotein substrateSubstrate0.7039
P-glycoprotein inhibitor INon-inhibitor0.8125
P-glycoprotein inhibitor IINon-inhibitor0.9824
Renal organic cation transporterNon-inhibitor0.8497
CYP450 2C9 substrateSubstrate0.622
CYP450 2D6 substrateNon-substrate0.8816
CYP450 3A4 substrateNon-substrate0.7268
CYP450 1A2 substrateNon-inhibitor0.9274
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9268
CYP450 2C19 inhibitorNon-inhibitor0.9104
CYP450 3A4 inhibitorNon-inhibitor0.84
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.962
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.8461
BiodegradationNot ready biodegradable0.7221
Rat acute toxicity1.8259 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8064
hERG inhibition (predictor II)Non-inhibitor0.8047
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Mass Spectrum (Electron Ionization)MSsplash10-06r6-9500000000-41e71d724a7515763bb7
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-001i-0119000000-08f98037ec7196f2922f
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00kg-6901000000-edb181b207ba0c040d5e

Taxonomy

Description
This compound belongs to the class of organic compounds known as benzenesulfonamides. These are organic compounds containing a sulfonamide group that is S-linked to a benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzenesulfonamides
Direct Parent
Benzenesulfonamides
Alternative Parents
Tosyl compounds / Benzenesulfonyl compounds / Sulfonylureas / Azepanes / Organosulfonic acids and derivatives / Aminosulfonyl compounds / Hydrazones / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds
show 2 more
Substituents
Benzenesulfonamide / Tosyl compound / Benzenesulfonyl group / Azepane / Toluene / Sulfonylurea / Organic sulfonic acid or derivatives / Organosulfonic acid or derivatives / Aminosulfonyl compound / Sulfonyl
show 12 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
N-sulfonylurea (CHEBI:9613)

Targets

Kind
Protein group
Organism
Human
Pharmacological action
Yes
Actions
Blocker
General Function
Sulfonylurea receptor activity
Specific Function
Subunit of the beta-cell ATP-sensitive potassium channel (KATP). Regulator of ATP-sensitive K(+) channels and insulin release.

Components:
References
  1. Szabo C, Salzman AL: Inhibition of ATP-activated potassium channels exerts pressor effects and improves survival in a rat model of severe hemorrhagic shock. Shock. 1996 Jun;5(6):391-4. [PubMed:8799949]
  2. Asano K, Cortes P, Garvin JL, Riser BL, Rodriguez-Barbero A, Szamosfalvi B, Yee J: Characterization of the rat mesangial cell type 2 sulfonylurea receptor. Kidney Int. 1999 Jun;55(6):2289-98. [PubMed:10354277]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. May M, Schindler C: Clinically and pharmacologically relevant interactions of antidiabetic drugs. Ther Adv Endocrinol Metab. 2016 Apr;7(2):69-83. doi: 10.1177/2042018816638050. Epub 2016 Mar 31. [PubMed:27092232]

Drug created on June 13, 2005 07:24 / Updated on August 10, 2018 11:09