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Identification
NameTorasemide
Accession NumberDB00214  (APRD00217, APRD00295)
Typesmall molecule
Groupsapproved
Description

Torasemide (rINN) or torsemide (USAN) is a pyridine-sulfonylurea type loop diuretic mainly used in the management of edema associated with congestive heart failure. It is also used at low doses for the management of hypertension. It is marketed under the brand name Demadex. [Wikipedia]

Structure
Thumb
Synonyms
SynonymLanguageCode
TorasemidaSpanishINN
TorasemidumLatinINN
TorsemideNot AvailableUSAN
SaltsNot Available
Brand names
NameCompany
DemadexNot Available
DiuverNot Available
ExamideNot Available
LupracNot Available
Brand mixturesNot Available
Categories
CAS number56211-40-6
WeightAverage: 348.42
Monoisotopic: 348.125611216
Chemical FormulaC16H20N4O3S
InChI KeyNGBFQHCMQULJNZ-UHFFFAOYSA-N
InChI
InChI=1S/C16H20N4O3S/c1-11(2)18-16(21)20-24(22,23)15-10-17-8-7-14(15)19-13-6-4-5-12(3)9-13/h4-11H,1-3H3,(H,17,19)(H2,18,20,21)
IUPAC Name
1-{4-[(3-methylphenyl)amino]pyridine-3-sulfonyl}-3-(propan-2-yl)urea
SMILES
CC(C)NC(=O)NS(=O)(=O)C1=C(NC2=CC=CC(C)=C2)C=CN=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassPyridines and Derivatives
SubclassPyridinesulfonamides
Direct parentPyridinesulfonamides
Alternative parentsToluenes; Sulfonylureas; Aminopyridines and Derivatives; Sulfonyls; Sulfonamides; Polyamines; Secondary Amines
Substituentsaminopyridine; toluene; sulfonylurea; benzene; sulfonyl; sulfonic acid derivative; sulfonamide; secondary amine; polyamine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the pyridinesulfonamides. These are heterocyclic compounds containing a pyridine ring substituted by one or more sulfonamide groups.
Pharmacology
IndicationFor the treatment of edema associated with congestive heart failure, renal disease, or hepatic disease. Also for the treatment of hypertension alone or in combination with other antihypertensive agents.
PharmacodynamicsTorasemide (INN) or torsemide (USAN) is a novel loop diuretic belonging to pridine sulphonyl urea. It differs form other thiazide diuretics in that a double ring system is incorporated into its structure. Like thiazides, loop diuretics must be secreted into the tubular fluid by proximal tubule cells. In the thick ascending loop Na+ and Cl- reabsorption is accomplished by a Na+/K+/2Cl- symporter. The thick ascending limb has a high reabsorptive capacity and is responsible for reabsorbing 25% of the filtered load of Na+. The loop diuretics act by blocking this symporter. Because of the large absorptive capacity and the amount of Na+ delivered to the ascending limb, loop diuretics have a profound diuretic action. In addition, more distal nephron segments do not have the reabsorptive capacity to compensate for this increased load. The osmotic gradient for water reabsorption is also reduced resulting in an increase in the amount of water excreted.
Mechanism of actionTorasemide inhibits the Na+/K+/2Cl--carrier system (via interference of the chloride binding site) in the lumen of the thick ascending portion of the loop of Henle, resulting in a decrease in reabsorption of sodium and chloride. This results in an increase in the rate of delivery of tubular fluid and electrolytes to the distal sites of hydrogen and potassium ion secretion, while plasma volume contraction increases aldosterone production. The increased delivery and high aldosterone levels promote sodium reabsorption at the distal tubules, and By increasing the delivery of sodium to the distal renal tubule, torasemide indirectly increases potassium excretion via the sodium-potassium exchange mechanism. Torasemide's effects in other segments of the nephron have not been demonstrated. Thus torasemide increases the urinary excretion of sodium, chloride, and water, but it does not significantly alter glomerular filtration rate, renal plasma flow, or acid-base balance. Torasemide's effects as a antihypertensive are due to its diuretic actions. By reducing extracellular and plasma fluid volume, blood pressure is reduced temporarily, and cardiac output also decreases.
AbsorptionRapidly absorbed following oral administration. Absolute bioavailability is 80%. Food has no effect on absorption.
Volume of distribution
  • 12 to 15 L [normal adults or in patients with mild to moderate renal failure or congestive heart failure]
Protein binding> 99%
Metabolism

Metabolized via the hepatic CYP2C8 to 5 metabolites. The major metabolite, M5, is pharmacologically inactive. There are 2 minor metabolites, M1, possessing one-tenth the activity of torasemide, and M3, equal in activity to torasemide. Overall, torasemide appears to account for 80% of the total diuretic activity, while metabolites M1 and M3 account for 9% and 11%, respectively.

SubstrateEnzymesProduct
Torasemide
hydroxytorsemideDetails
Route of eliminationTorsemide is cleared from the circulation by both hepatic metabolism (approximately 80% of total clearance) and excretion into the urine (approximately 20% of total clearance in patients with normal renal function).
Half life3.5 hours
ClearanceNot Available
ToxicitySymptoms of overdose include dehydration, hypovolemia, hypotension, hyponatremia, hypokalemia, hypochloremic alkalosis, and hemoconcentration. Oral LD50 in rat is 5 g/kg, and intravenous LD50 in rat is 500 mg/kg.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Torsemide Action PathwayDrug actionSMP00118
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9156
Blood Brain Barrier + 0.6871
Caco-2 permeable - 0.5374
P-glycoprotein substrate Non-substrate 0.799
P-glycoprotein inhibitor I Non-inhibitor 0.7695
P-glycoprotein inhibitor II Non-inhibitor 0.8232
Renal organic cation transporter Non-inhibitor 0.9185
CYP450 2C9 substrate Substrate 0.6049
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Non-substrate 0.7558
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.6692
CYP450 2D6 substrate Non-inhibitor 0.923
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Inhibitor 0.5905
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6324
Ames test Non AMES toxic 0.9133
Carcinogenicity Non-carcinogens 0.8366
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 1.8740 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9854
hERG inhibition (predictor II) Non-inhibitor 0.8668
Pharmacoeconomics
Manufacturers
  • Hoffmann la roche inc
  • Bedford laboratories
  • Luitpold pharmaceuticals inc
  • Meda pharmaceuticals inc
  • Apotex inc etobicoke site
  • Aurobindo pharma ltd
  • Hetero drugs ltd
  • Par pharmaceutical inc
  • Pliva pharmaceutical industry inc
  • Roxane laboratories inc
  • Sun pharmaceutical industries ltd
  • Teva pharmaceuticals usa inc
Packagers
Dosage forms
FormRouteStrength
Injection, solutionIntravenous
TabletOral
Prices
Unit descriptionCostUnit
Demadex 100 mg tablet5.69USDtablet
Torsemide 100 mg tablet3.16USDtablet
Demadex 20 mg tablet1.59USDtablet
Demadex 10 mg tablet1.39USDtablet
Demadex 5 mg tablet1.28USDtablet
Torsemide 20 mg tablet0.85USDtablet
Torsemide 10 mg tablet0.73USDtablet
Torsemide 5 mg tablet0.66USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point164-164 °CNot Available
water solubilityWater solubleNot Available
logP2.3Not Available
pKa7.1Not Available
Predicted Properties
PropertyValueSource
water solubility5.96e-02 g/lALOGPS
logP1.76ALOGPS
logP1.86ChemAxon
logS-3.8ALOGPS
pKa (strongest acidic)5.92ChemAxon
pKa (strongest basic)4.2ChemAxon
physiological charge-1ChemAxon
hydrogen acceptor count5ChemAxon
hydrogen donor count3ChemAxon
polar surface area100.19ChemAxon
rotatable bond count4ChemAxon
refractivity91.89ChemAxon
polarizability36.15ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Fritz Topfmeier, Gustav Lettenbauer, “Process for the preparation of a stable modification of torasemide.” U.S. Patent USRE0345806, issued June, 1975.

USRE0345806
General Reference
  1. Dunn CJ, Fitton A, Brogden RN: Torasemide. An update of its pharmacological properties and therapeutic efficacy. Drugs. 1995 Jan;49(1):121-42. Pubmed
  2. FDA approved new drug bulletin: torsemide (Demadex), trimetrexate glucuronate (neuTrexin). RN. 1994 May;57(5):53-6. Pubmed
External Links
ResourceLink
KEGG DrugD00382
PubChem Compound41781
PubChem Substance46504760
ChemSpider38123
Therapeutic Targets DatabaseDAP000745
PharmGKBPA451733
Drug Product Database2129094
RxListhttp://www.rxlist.com/cgi/generic/demadex.htm
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/dem1634.shtml
WikipediaTorasemide
ATC CodesC03CA01C03CA04
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(110 KB)
Interactions
Drug Interactions
Drug
AmifostineTorasemide may increase the hypotensive effect of Amifostine. At chemotherapeutic doses of Amifostine, Torasemide should be withheld for 24 hours prior to Amifostine administration. Use caution at lower doses of Amifostine.
AmikacinIncreased ototoxicity
CapecitabineCapecitabine, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Capecitabine is initiated, discontinued or dose changed.
CholestyramineCholestyramine may decrease the bioavailability of Torasemide by inhibiting Torasemide absorption. Monitor for changes in the therapeutic and adverse effects of Torasemide if Cholestyramine is initiated, discontinued or dose changed. Spacing administration by at least 2 hours may reduce the risk of interaction.
ColesevelamColesevelam may decrease the bioavailability of Torasemide by inhibiting Torasemide absorption. Monitor for changes in the therapeutic and adverse effects of Torasemide if Colesevelam is initiated, discontinued or dose changed. Spacing administration by at least 2 hours may reduce the risk of interaction.
ColestipolColestipol may decrease the bioavailability of Torasemide by inhibiting Torasemide absorption. Monitor for changes in the therapeutic and adverse effects of Torasemide if Colestipol is initiated, discontinued or dose changed. Spacing administration by at least 2 hours may reduce the risk of interaction.
DelavirdineDelavirdine, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Delavirdine is initiated, discontinued or dose changed.
FloxuridineFloxuridine, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Floxuridine is initiated, discontinued or dose changed.
FluconazoleFluconazole, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Fluconazole is initiated, discontinued or dose changed.
FluorouracilFluorouracil, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Fluorouracil is initiated, discontinued or dose changed.
FlurbiprofenFlurbiprofen, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Flurbiprofen is initiated, discontinued or dose changed.
GemfibrozilGemfibrozil, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Gemfibrozil is initiated, discontinued or dose changed.
GentamicinIncreased ototoxicity
IbuprofenThe NSAID, ibuprofen, may decrease the diuretic and antihypertensive effect of the loop diuretic, torasemide.
IndomethacinThe NSAID, indomethacin, may decrease the diuretic and antihypertensive effects of the loop diuretic, torasemide.
KetoconazoleKetoconazole, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Ketoconazole is initiated, discontinued or dose changed.
Mefenamic acidMefanamic acid, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Mefanamic acid is initiated, discontinued or dose changed.
MiconazoleMiconazole, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Miconazole is initiated, discontinued or dose changed.
NetilmicinIncreased ototoxicity
NicardipineNicardipine, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Nicardipine is initiated, discontinued or dose changed.
PiroxicamPiroxicam, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Piroxicam is initiated, discontinued or dose changed.
RituximabAdditive antihypertensive effects may occur. Increased risk of hypotension. Consider withholding Torasemide for 12 hours prior to administration of Rituximab.
SitaxentanSitaxsentan, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Sitaxsentan is initiated, discontinued or dose changed.
SulfadiazineSulfadiazine, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Sulfadiazine is initiated, discontinued or dose changed.
SulfisoxazoleSulfisoxazole, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Sulfisoxazole is initiated, discontinued or dose changed.
TobramycinIncreased ototoxicity
TolbutamideTolbutamide, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing its metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Tolbutamide is initiated, discontinued or dose changed.
TrandolaprilThe loop diuretic, Torasemide, may increase the hypotensive effect of Trandolapril. Torasemide may also increase the nephrotoxicity of Trandolapril.
TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Food InteractionsNot Available

Targets

1. Solute carrier family 12 member 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier family 12 member 1 Q13621 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Vormfelde SV, Sehrt D, Toliat MR, Schirmer M, Meineke I, Tzvetkov M, Nurnberg P, Brockmoller J: Genetic variation in the renal sodium transporters NKCC2, NCC, and ENaC in relation to the effects of loop diuretic drugs. Clin Pharmacol Ther. 2007 Sep;82(3):300-9. Epub 2007 Apr 25. Pubmed
  3. Fortuno A, Muniz P, Ravassa S, Rodriguez JA, Fortuno MA, Zalba G, Diez J: Torasemide inhibits angiotensin II-induced vasoconstriction and intracellular calcium increase in the aorta of spontaneously hypertensive rats. Hypertension. 1999 Jul;34(1):138-43. Pubmed

Enzymes

1. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Prostaglandin G/H synthase 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Prostaglandin G/H synthase 1 P23219 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

4. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 25, 2013 12:39