Tolazamide

Identification

Summary

Tolazamide is a sulfonylurea used in the treatment of non insulin dependent diabetes mellitus.

Brand Names
Tolinase
Generic Name
Tolazamide
DrugBank Accession Number
DB00839
Background

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

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 311.4
Monoisotopic: 311.130362243
Chemical Formula
C14H21N3O3S
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

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.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofType 2 diabetes mellitus••••••••••••
Contraindications & Blackbox Warnings
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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.

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
Humans
AATP-sensitive inward rectifier potassium channel 10
blocker
Humans
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

Adverse Effects
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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.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirTolazamide may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbataceptThe metabolism of Tolazamide can be increased when combined with Abatacept.
AbrocitinibThe metabolism of Abrocitinib can be decreased when combined with Tolazamide.
AcarboseThe risk or severity of hypoglycemia can be increased when Acarbose is combined with Tolazamide.
AcebutololThe therapeutic efficacy of Tolazamide can be increased when used in combination with Acebutolol.
Food Interactions
  • Avoid excessive or chronic alcohol consumption. Ingesting alcohol may increase the risk of hypoglycemia.
  • Take with food. Taking tolazamide with breakfast may help reduce the risk of hypoglycemia.

Products

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International/Other Brands
Desumide (Hua Shin) / Diabewas / Esulin (Chung Mei) / Norglycin (Pfizer) / Tolanase (Upjohn)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TolazamideTablet100 mg/1OralMutual Pharmaceutical Company2007-03-30Not applicableUS flag
TolazamideTablet500 mg/1OralMutual Pharmaceutical Company2007-03-30Not applicableUS flag
TolazamideTablet250 mg/1OralMutual Pharmaceutical Company2007-03-30Not applicableUS flag
TolinaseTablet500 mg/1OralUNSPECIFIED2006-04-11Not applicableUS flag
TolinaseTablet250 mg/1OralUNSPECIFIED2006-04-11Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TolazamideTablet250 mg/1OralMylan Pharmaceuticals Inc.2013-01-182020-03-31US flag
TolazamideTablet500 mg/1OralMylan Pharmaceuticals Inc.2013-01-182020-03-31US flag
TolazamideTablet250 mg/1OralAmerincan Health Packaging2012-02-132015-05-31US flag
TolazamideTablet250 mg/1OralPD-Rx Pharmaceuticals, Inc.2010-01-052019-09-11US flag
TolazamideTablet250 mg/1OralPhysicians Total Care, Inc.1995-02-022012-06-30US flag

Categories

ATC Codes
A10BB05 — TolazamideG01AE10 — Combinations of sulfonamides
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Aminosulfonyl compound / Aromatic heteromonocyclic compound / Azacycle / Azepane / Benzenesulfonamide / Benzenesulfonyl group / Hydrazone / Hydrocarbon derivative / Organic nitrogen compound / Organic oxide
show 12 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
N-sulfonylurea (CHEBI:9613)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
9LT1BRO48Q
CAS number
1156-19-0
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

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. [Article]
  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. [Article]
  3. DailyMed: TOLINASE (tolazamide) tablets [Link]
Human Metabolome Database
HMDB0014977
KEGG Drug
D00379
PubChem Compound
5503
PubChem Substance
46505642
ChemSpider
5302
BindingDB
50240099
RxNav
10633
ChEBI
9613
ChEMBL
CHEMBL817
ZINC
ZINC000000057512
Therapeutic Targets Database
DAP000919
PharmGKB
PA164774902
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Tolazamide

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableCompletedNot AvailableType 2 Diabetes Mellitus3somestatusstop reasonjust information to hide
2CompletedTreatmentImpaired Glucose Tolerance / Type 2 Diabetes Mellitus1somestatusstop reasonjust information to hide

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-MSsplash10-0007-9530000000-1efba84cf35a7c3462e8
Mass Spectrum (Electron Ionization)MSsplash10-06r6-9500000000-41e71d724a7515763bb7
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-001i-0119000000-08f98037ec7196f2922f
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-00kg-6901000000-edb181b207ba0c040d5e
MS/MS Spectrum - , positiveLC-MS/MSsplash10-001i-0119000000-08f98037ec7196f2922f
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00kg-6901000000-edb181b207ba0c040d5e
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-03di-3509000000-6fbe3e8f4082202cedd3
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-03di-0309000000-e4f0d2af036d83a45913
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-01ox-9404000000-cc1c3732674bf335a058
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-00di-1900000000-2da9231d245a9330f144
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-9001000000-7a28096839a1768ee443
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-006x-9800000000-84bf8375e6d33701f92d
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-181.6095776
predicted
DarkChem Lite v0.1.0
[M-H]-177.5293901
predicted
DarkChem Lite v0.1.0
[M-H]-188.5330776
predicted
DarkChem Lite v0.1.0
[M-H]-168.91322
predicted
DeepCCS 1.0 (2019)
[M+H]+182.8526776
predicted
DarkChem Lite v0.1.0
[M+H]+177.7627339
predicted
DarkChem Lite v0.1.0
[M+H]+189.1580776
predicted
DarkChem Lite v0.1.0
[M+H]+171.30885
predicted
DeepCCS 1.0 (2019)
[M+Na]+182.0320776
predicted
DarkChem Lite v0.1.0
[M+Na]+181.0448776
predicted
DarkChem Lite v0.1.0
[M+Na]+188.4193776
predicted
DarkChem Lite v0.1.0
[M+Na]+177.34247
predicted
DeepCCS 1.0 (2019)

Targets

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

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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Blocker
General Function
May be responsible for potassium buffering action of glial cells in the brain. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium and cesium (By similarity). In the kidney, together with KCNJ16, mediates basolateral K(+) recycling in distal tubules; this process is critical for Na(+) reabsorption at the tubules
Specific Function
ATP binding
Gene Name
KCNJ10
Uniprot ID
P78508
Uniprot Name
ATP-sensitive inward rectifier potassium channel 10
Molecular Weight
42507.71 Da
References
  1. Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
Specific Function
(R)-limonene 6-monooxygenase activity
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. [Article]

Drug created at June 13, 2005 13:24 / Updated at August 26, 2024 19:23