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Identification
NameBosentan
Accession NumberDB00559  (APRD00829)
Typesmall molecule
Groupsapproved, investigational
Description

Bosentan is a dual endothelin receptor antagonist important in the treatment of pulmonary artery hypertension (PAH). It is licensed in the United States, the European Union and other countries by Actelion Pharmaceuticals for the management of PAH under the trade name Tracleer®. Bosentan is used to treat pulmonary hypertension by blocking the action of endothelin molecules that would otherwise promote narrowing of the blood vessels and lead to high blood pressure.

Structure
Thumb
Synonyms
SynonymLanguageCode
Bosentan hydrateNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
TracleerActelion
Brand mixturesNot Available
Categories
CAS number147536-97-8
WeightAverage: 551.614
Monoisotopic: 551.183854375
Chemical FormulaC27H29N5O6S
InChI KeyInChIKey=GJPICJJJRGTNOD-UHFFFAOYSA-N
InChI
InChI=1S/C27H29N5O6S/c1-27(2,3)18-10-12-19(13-11-18)39(34,35)32-23-22(38-21-9-6-5-8-20(21)36-4)26(37-17-16-33)31-25(30-23)24-28-14-7-15-29-24/h5-15,33H,16-17H2,1-4H3,(H,30,31,32)
IUPAC Name
4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]benzene-1-sulfonamide
SMILES
COC1=CC=CC=C1OC1=C(NS(=O)(=O)C2=CC=C(C=C2)C(C)(C)C)N=C(N=C1OCCO)C1=NC=CC=N1
Mass SpecNot Available
Taxonomy
KingdomNot Available
SuperclassNot Available
ClassNot Available
SubclassNot Available
Direct parentNot Available
Alternative parentsNot Available
SubstituentsNot Available
Classification descriptionNot Available
Pharmacology
IndicationUsed in the treatment of pulmonary arterial hypertension (PAH), to improve exercise ability and to decrease the rate of clinical worsening (in patients with WHO Class III or IV symptoms).
PharmacodynamicsBosentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Bosentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects.
Mechanism of actionEndothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ETA and ETB receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentan is a specific and competitive antagonist at endothelin receptor types ETA and ETB. Bosentan has a slightly higher affinity for ETA receptors than for ETB receptors.
AbsorptionAbsolute bioavailability is approximately 50% and food does not affect absorption.
Volume of distribution
  • 18 L
Protein bindingGreater than 98% to plasma proteins, mainly albumin.
Metabolism

Bosentan is metabolized in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 (and possibly CYP2C19), producing three metabolites, one of which, Ro 48-5033, is pharmacologically active and may contribute 10 to 20% to the total activity of the parent compound.

SubstrateEnzymesProduct
Bosentan
Bosentan metabolite Ro 48-5033Details
Bosentan
Bosentan metabolite Ro 47-8634Details
Bosentan metabolite Ro 48-5033
    Bosentan metabolite Ro 64-1056Details
    Bosentan metabolite Ro 47-8634
      Bosentan metabolite Ro 64-1056Details
      Route of eliminationBosentan is eliminated by biliary excretion following metabolism in the liver.
      Half lifeTerminal elimination half-life is about 5 hours in healthy adult subjects.
      Clearance
      • 4 L/h [patients with pulmonary arterial hypertension]
      ToxicityBosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support.
      Affected organisms
      • Humans and other mammals
      PathwaysNot Available
      SNP Mediated EffectsNot Available
      SNP Mediated Adverse Drug ReactionsNot Available
      ADMET
      Predicted ADMET features
      Property Value Probability
      Human Intestinal Absorption + 0.9253
      Blood Brain Barrier - 0.7419
      Caco-2 permeable - 0.8956
      P-glycoprotein substrate Non-substrate 0.5738
      P-glycoprotein inhibitor I Non-inhibitor 0.6175
      P-glycoprotein inhibitor II Non-inhibitor 0.5092
      Renal organic cation transporter Non-inhibitor 0.9149
      CYP450 2C9 substrate Non-substrate 0.5926
      CYP450 2D6 substrate Non-substrate 0.9117
      CYP450 3A4 substrate Substrate 0.5132
      CYP450 1A2 substrate Non-inhibitor 0.7203
      CYP450 2C9 substrate Inhibitor 0.518
      CYP450 2D6 substrate Non-inhibitor 0.8755
      CYP450 2C19 substrate Non-inhibitor 0.5219
      CYP450 3A4 substrate Inhibitor 0.8407
      CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.772
      Ames test Non AMES toxic 0.6147
      Carcinogenicity Non-carcinogens 0.6515
      Biodegradation Not ready biodegradable 1.0
      Rat acute toxicity 2.2676 LD50, mol/kg Not applicable
      hERG inhibition (predictor I) Weak inhibitor 0.9679
      hERG inhibition (predictor II) Non-inhibitor 0.572
      Pharmacoeconomics
      Manufacturers
      • Actelion ltd
      Packagers
      Dosage forms
      FormRouteStrength
      Tablet, film coatedOral125 mg
      Tablet, film coatedOral62.5 mg
      PricesNot Available
      Patents
      CountryPatent NumberApprovedExpires (estimated)
      United States52927401995-11-202015-11-20
      Canada20711931998-08-252012-06-12
      Properties
      Statesolid
      Experimental Properties
      PropertyValueSource
      water solubilityPoorly soluble in water (1.0 mg/100 ml) and in aqueous solutions at low pH (0.1 mg/100 ml at pH 1.1 and 4.0; 0.2 mg/100 ml at pH 5.0). Solubility increases at higher pH values (43 mg/100 ml at pH 7.5).Not Available
      logP3.7Not Available
      Caco2 permeability-5.98ADME Research, USCD
      Predicted Properties
      PropertyValueSource
      water solubility9.04e-03 g/lALOGPS
      logP4.18ALOGPS
      logP4.94ChemAxon
      logS-4.8ALOGPS
      pKa (strongest acidic)5.8ChemAxon
      pKa (strongest basic)-0.43ChemAxon
      physiological charge-1ChemAxon
      hydrogen acceptor count9ChemAxon
      hydrogen donor count2ChemAxon
      polar surface area145.65ChemAxon
      rotatable bond count10ChemAxon
      refractivity166.66ChemAxon
      polarizability57.89ChemAxon
      number of rings4ChemAxon
      bioavailability1ChemAxon
      rule of fiveNoChemAxon
      Ghose filterNoChemAxon
      Veber's ruleNoChemAxon
      MDDR-like ruleYesChemAxon
      Spectra
      SpectraNot Available
      References
      Synthesis Reference

      Maurizio TADDEI, Diletta Naldini, Pietro Allegrini, Gabriele Razzetti, Simone Mantegazza, “Process for the Preparation of Bosentan.” U.S. Patent US20090156811, issued June 18, 2009.

      US20090156811
      General ReferenceNot Available
      External Links
      ResourceLink
      KEGG DrugD01227
      PubChem Compound104865
      PubChem Substance46507154
      ChemSpider94651
      ChEBI51450
      ChEMBLCHEMBL957
      Therapeutic Targets DatabaseDNC000341
      PharmGKBPA10034
      Drug Product Database2244982
      RxListhttp://www.rxlist.com/cgi/generic3/tracleer.htm
      Drugs.comhttp://www.drugs.com/cdi/bosentan.html
      WikipediaBosentan
      ATC CodesC02KX01
      AHFS Codes
      • 24:12.92
      PDB EntriesNot Available
      FDA labelshow(424 KB)
      MSDSNot Available
      Interactions
      Drug Interactions
      Drug
      AcenocoumarolBosentan may decrease the anticoagulant effect of acenocoumarol by increasing its metabolism.
      AnisindioneBosentan may decrease the anticoagulant effect of anisindione by increasing its metabolism.
      AtorvastatinBosentan may decrease the serum concentration of atorvastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if bosentan is initiated, discontinued or dose changed.
      CerivastatinBosentan may decrease the serum concentration of cerivastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of cerivastatin if bosentan is initiated, discontinued or dose changed.
      CyclosporineCyclosporine may increase the effect and toxicity of bosentan.
      DicoumarolBosentan may decrease the anticoagulant effect of dicumarol by increasing its metabolism.
      Estradiol valerate/DienogestAffects CYP3A4 metabolism, decreases or effects levels of Estradiol valerate/Dienogest.
      Ethinyl EstradiolBosentan may decrease the contraceptive effect of ethinyl estradiol. Hormonal contraception should not be relied on alone during concomitant therapy with bosentan.
      GlyburideIncreased risk of hepatic toxicity
      ItraconazoleItraconazole may increase the effect and toxicity of bosentan.
      KetoconazoleKetoconazole may increase the effect and toxicity of bosentan.
      LovastatinBosentan may decrease the serum concentration of lovastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of lovastatin if bosentan is initiated, discontinued or dose changed.
      LurasidoneConcomitant therapy with a CYP3A4 substrate and inducer will decrease levels of lurasidone. Coadministration with lurasidone is contraindicated.
      Medroxyprogesterone AcetateBosentan may decrease the contraceptive effect of medroxyprogesterone. Hormonal contraception should not be relied on alone during concomitant therapy with bosentan.
      MestranolDecreases the effect of contraceptive
      NorethindroneBosentan may decrease the contraceptive effect of norethindrone. Hormonal contraception should not be relied on alone during concomitant therapy with bosentan.
      RoflumilastAffects CYP3A4 metabolism, decreases level or effect of roflumilast.
      SimvastatinBosentan may decrease the serum concentration of simvastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of simvastatin if bosentan is initiated, discontinued or dose changed.
      TelithromycinCo-administration may cause decreased Telithromycin and increased Bosentan plasma concentrations. Consider alternate therapy.
      TemsirolimusBosentan may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
      TolbutamideTolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Bosentan. Consider alternate therapy or monitor for changes in Bosentan therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
      TramadolBosentan may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
      TrazodoneThe CYP3A4 inducer, Bosentan, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Bosentan is initiated, discontinued or dose changed.
      UlipristalConcomitant therapy with strong CYP3A4 inducers may decrease plasma concentrations of ulipristal and ultimately its effectiveness. Avoid combination therapy.
      VandetanibDecreases levels of vandetanib by affecting CYP3A4 metabolism. Contraindicated.
      VoriconazoleVoriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of bosentan by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of bosentan if voriconazole is initiated, discontinued or dose changed.
      WarfarinBosentan may decrease the anticoagulant effect of warfarin by increasing its metabolism.
      Food Interactions
      • Take without regard to meals.

      1. Endothelin-1 receptor

      Kind: protein

      Organism: Human

      Pharmacological action: yes

      Actions: antagonist

      Components

      Name UniProt ID Details
      Endothelin-1 receptor P25101 Details

      References:

      1. Albertini M, Lafortuna CL, Ciminaghi B, Mazzola S, Clement MG: Endothelin involvement in respiratory centre activity. Prostaglandins Leukot Essent Fatty Acids. 2001 Sep;65(3):157-63. Pubmed
      2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
      3. Kiowski W, Sutsch G, Oechslin E, Bertel O: Hemodynamic effects of bosentan in patients with chronic heart failure. Heart Fail Rev. 2001 Dec;6(4):325-34. Pubmed
      4. Kramp R, Fourmanoir P, Caron N: Endothelin resets renal blood flow autoregulatory efficiency during acute blockade of NO in the rat. Am J Physiol Renal Physiol. 2001 Dec;281(6):F1132-40. Pubmed
      5. Martin C, Held HD, Uhlig S: Differential effects of the mixed ET/ET-receptor antagonist bosentan on endothelin-induced bronchoconstriction, vasoconstriction and prostacyclin release. Naunyn Schmiedebergs Arch Pharmacol. 2000 Aug;362(2):128-36. Pubmed
      6. Sihvola RK, Pulkkinen VP, Koskinen PK, Lemstrom KB: Crosstalk of endothelin-1 and platelet-derived growth factor in cardiac allograft arteriosclerosis. J Am Coll Cardiol. 2002 Feb 20;39(4):710-7. Pubmed

      2. Endothelin B receptor

      Kind: protein

      Organism: Human

      Pharmacological action: yes

      Actions: antagonist

      Components

      Name UniProt ID Details
      Endothelin B receptor P24530 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. Gardiner SM, Kemp PA, March JE, Bennett T: Effects of bosentan (Ro 47-0203), an ETA-, ETB-receptor antagonist, on regional haemodynamic responses to endothelins in conscious rats. Br J Pharmacol. 1994 Jul;112(3):823-30. Pubmed
      3. Gupta SK, Saxena A, Singh U, Arya DS: Bosentan, the mixed ETA-ETB endothelin receptor antagonist, attenuated oxidative stress after experimental myocardial ischemia and reperfusion. Mol Cell Biochem. 2005 Jul;275(1-2):67-74. Pubmed
      4. Marano G, Palazzesi S, Bernucci P, Grigioni M, Formigari R, Ballerini L: ET/ET receptor antagonist bosentan inhibits neointimal development in collared carotid arteries of rabbits. Life Sci. 1998;63(18):PL259-66. Pubmed
      5. Richard V, Kaeffer N, Hogie M, Tron C, Blanc T, Thuillez C: Role of endogenous endothelin in myocardial and coronary endothelial injury after ischaemia and reperfusion in rats: studies with bosentan, a mixed ETA-ETB antagonist. Br J Pharmacol. 1994 Nov;113(3):869-76. Pubmed
      6. Said SA, Ammar el SM, Suddek GM: Effect of bosentan (ETA/ETB receptor antagonist) on metabolic changes during stress and diabetes. Pharmacol Res. 2005 Feb;51(2):107-15. Pubmed

      1. Cytochrome P450 3A4

      Kind: protein

      Organism: Human

      Pharmacological action: unknown

      Actions: substrate inducer

      Components

      Name UniProt ID Details
      Cytochrome P450 3A4 P08684 Details

      References:

      1. Dingemanse J, Schaarschmidt D, van Giersbergen PL: Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin. Clin Pharmacokinet. 2003;42(3):293-301. Pubmed
      2. Dingemanse J, van Giersbergen PL: Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet. 2004;43(15):1089-115. Pubmed
      3. 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. 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 inducer

      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. 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

      1. Bile salt export pump

      Kind: protein

      Organism: Human

      Pharmacological action: unknown

      Actions: inhibitor

      Components

      Name UniProt ID Details
      Bile salt export pump O95342 Details

      References:

      1. Fattinger K, Funk C, Pantze M, Weber C, Reichen J, Stieger B, Meier PJ: The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther. 2001 Apr;69(4):223-31. Pubmed

      Comments
      Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11