Banner
targets (1) enzymes (4)
for drugs
Identification
Name Torasemide
Accession Number DB00214 (APRD00217, APRD00295)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Torasemida [INN-Spanish]
  • Torasemidum [INN-Latin]
  • Torsemide
Brand names
  • Demadex
  • Luprac
Brand name mixtures Not Available
Categories
  • Antihypertensive Agents
  • Diuretics
CAS number 56211-40-6
Weight Average: 348.42
Monoisotopic: 348.125611216
Chemical Formula C16H20N4O3S
InChI Key InChIKey=NGBFQHCMQULJNZ-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)
Plain Text
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(C)=CC=C2)C=CN=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Sulfonylureas
Substructures
  • Sulfonylureas
  • Aliphatic and Aryl Amines
  • Pyridines and Derivatives
  • Sulfonyls
  • Benzene and Derivatives
  • Ureas and Derivatives
  • Aminopyridines and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Sulfonamides
  • Anilines
Pharmacology
Indication For 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.
Pharmacodynamics Torasemide (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 action Torasemide 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.
Absorption Rapidly 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.

Enzyme Metabolite Reaction Km Vmax
Prostaglandin G/H synthase 1 hydroxylation
Cytochrome P450 2C9 methyl-hydroxylation
Cytochrome P450 2C9 hydroxytorsemide tolylmethylhydroxylation 11.9 136.61
Cytochrome P450 2C8 hydroxytorsemide tolylmethylhydroxylation 147 32.22
Route of elimination Torsemide 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 life 3.5 hours
Clearance Not Available
Toxicity Symptoms 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
Pathway Name SMPDB ID
Smp00118 Torsemide Pathway SMP00118
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
Form Route Strength
Injection, solution Intravenous
Tablet Oral
Prices
Unit description Cost Unit
Demadex 100 mg tablet 5.69 USD tablet
Torsemide 100 mg tablet 3.16 USD tablet
Demadex 20 mg tablet 1.59 USD tablet
Demadex 10 mg tablet 1.39 USD tablet
Demadex 5 mg tablet 1.28 USD tablet
Torsemide 20 mg tablet 0.85 USD tablet
Torsemide 10 mg tablet 0.73 USD tablet
Torsemide 5 mg tablet 0.66 USD tablet
Patents Not Available
Properties
State solid
Melting point 164-164 oC
Experimental Properties
Property Value Source
water solubility Water soluble PhysProp
logP 2.3 PhysProp
pKa 7.1 Various sources
Predicted Properties
Property Value Source
water solubility 5.96e-02 g/l ALOGPS
logP 1.76 ALOGPS
logP 1.86 ChemAxon Molconvert
logS -3.77 ALOGPS
pKa 16.74 ChemAxon Molconvert
hydrogen acceptor count 5 ChemAxon Molconvert
hydrogen donor count 3 ChemAxon Molconvert
polar surface area 100.19 ChemAxon Molconvert
rotatable bond count 4 ChemAxon Molconvert
refractivity 91.89 ChemAxon Molconvert
polarizability 36.15 ChemAxon Molconvert
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D00382 Link_out
PubChem Compound 41781 Link_out
PubChem Substance 46504760 Link_out
ChemSpider 38123 Link_out
Therapeutic Targets Database DAP000745 Link_out
PharmGKB PA451733 Link_out
Drug Product Database 2129094 Link_out
RxList http://www.rxlist.com/cgi/generic/demadex.htm Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/dem1634.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Torasemide Link_out
ATC Codes
  • C03CA01
  • C03CA04
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS show (110.1 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Solute carrier family 12 member 1

Pharmacological action: yes
Actions: inhibitor

Electrically silent transporter system. Mediates sodium and chloride reabsorption. Plays a vital role in the regulation of ionic balance and cell volume

Organism class: human
UniProt ID: Q13621 Link_out
Gene: SLC12A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

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 unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol)

UniProt ID: P10632 Link_out
Gene: CYP2C8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

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 unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

May play an important role in regulating or promoting cell proliferation in some normal and neoplastically transformed cells

UniProt ID: P23219 Link_out
Gene: PTGS1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:37

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.