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Identification
Name Bosentan
Accession Number DB00559 (APRD00829)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Bosentan hydrate
Salts Not Available
Brand names
Name Company
Tracleer Actelion
Brand mixtures Not Available
Categories
  • Antihypertensive Agents
CAS number 147536-97-8
Weight Average: 551.614
Monoisotopic: 551.183854375
Chemical Formula C27H29N5O6S
InChI Key InChIKey=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)
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Cumenes and Derivatives
  • Benzenesulfonamides
Substructures
  • Hydroxy Compounds
  • Phenols and Derivatives
  • Sulfonyls
  • Ethers
  • Benzene and Derivatives
  • Cumenes and Derivatives
  • Benzenesulfonamides
  • Alcohols and Polyols
  • Pyrimidines and Derivatives
  • Catechols
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Sulfonamides
  • Imines
  • Cyanamides
  • Phenyl Esters
Pharmacology
Indication Used 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).
Pharmacodynamics Bosentan 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 action Endothelin-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.
Absorption Absolute bioavailability is approximately 50% and food does not affect absorption.
Volume of distribution
  • 18 L
Protein binding Greater 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.
Route of elimination Bosentan is eliminated by biliary excretion following metabolism in the liver.
Half life Terminal elimination half-life is about 5 hours in healthy adult subjects.
Clearance
  • 4 L/h [patients with pulmonary arterial hypertension]
Toxicity Bosentan 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
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Actelion ltd
Packagers
Dosage forms
Form Route Strength
Tablet, film coated Oral 125 mg
Tablet, film coated Oral 62.5 mg
Prices Not Available
Patents
Country Patent Number Approved Expires (estimated)
United States 5292740 1995-11-20 2015-11-20
Canada 2071193 1998-08-25 2012-06-12
Properties
State solid
Experimental Properties
Property Value Source
water solubility Poorly 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
logP 3.7 Not Available
Caco2 permeability -5.98 ADME Research, USCD
Predicted Properties
Property Value Source
water solubility 9.04e-03 g/l ALOGPS
logP 4.18 ALOGPS
logP 4.94 ChemAxon
logS -4.8 ALOGPS
pKa (strongest acidic) 5.8 ChemAxon
pKa (strongest basic) -0.43 ChemAxon
physiological charge -1 ChemAxon
hydrogen acceptor count 9 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 145.65 ChemAxon
rotatable bond count 10 ChemAxon
refractivity 166.66 ChemAxon
polarizability 57.89 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D01227 Link_out
PubChem Compound 104865 Link_out
PubChem Substance 46507154 Link_out
ChemSpider 94651 Link_out
ChEBI 51450 Link_out
ChEMBL 51450 Link_out
Therapeutic Targets Database DNC000341 Link_out
PharmGKB PA10034 Link_out
Drug Product Database 2244982 Link_out
RxList http://www.rxlist.com/cgi/generic3/tracleer.htm Link_out
Drugs.com http://www.drugs.com/cdi/bosentan.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Bosentan Link_out
ATC Codes
  • C02KX01
AHFS Codes
  • 24:12.92
PDB Entries Not Available
FDA label show (424 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Acenocoumarol Bosentan may decrease the anticoagulant effect of acenocoumarol by increasing its metabolism.
Anisindione Bosentan may decrease the anticoagulant effect of anisindione by increasing its metabolism.
Atorvastatin Bosentan 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.
Cerivastatin Bosentan 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.
Cyclosporine Cyclosporine may increase the effect and toxicity of bosentan.
Dicumarol Bosentan may decrease the anticoagulant effect of dicumarol by increasing its metabolism.
Estradiol valerate/Dienogest Affects CYP3A4 metabolism, decreases or effects levels of Estradiol valerate/Dienogest.
Ethinyl Estradiol Bosentan may decrease the contraceptive effect of ethinyl estradiol. Hormonal contraception should not be relied on alone during concomitant therapy with bosentan.
Glyburide Increased risk of hepatic toxicity
Itraconazole Itraconazole may increase the effect and toxicity of bosentan.
Ketoconazole Ketoconazole may increase the effect and toxicity of bosentan.
Lovastatin Bosentan 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.
Lurasidone Concomitant therapy with a CYP3A4 substrate and inducer will decrease levels of lurasidone. Coadministration with lurasidone is contraindicated.
Medroxyprogesterone Bosentan may decrease the contraceptive effect of medroxyprogesterone. Hormonal contraception should not be relied on alone during concomitant therapy with bosentan.
Mestranol Decreases the effect of contraceptive
Norethindrone Bosentan may decrease the contraceptive effect of norethindrone. Hormonal contraception should not be relied on alone during concomitant therapy with bosentan.
Roflumilast Affects CYP3A4 metabolism, decreases level or effect of roflumilast.
Simvastatin Bosentan 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.
Telithromycin Co-administration may cause decreased Telithromycin and increased Bosentan plasma concentrations. Consider alternate therapy.
Temsirolimus Bosentan may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Tolbutamide Tolbutamide, 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.
Tramadol Bosentan may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
Trazodone The 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.
Ulipristal Concomitant therapy with strong CYP3A4 inducers may decrease plasma concentrations of ulipristal and ultimately its effectiveness. Avoid combination therapy.
Vandetanib Decreases levels of vandetanib by affecting CYP3A4 metabolism. Contraindicated.
Voriconazole Voriconazole, 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.
Warfarin Bosentan may decrease the anticoagulant effect of warfarin by increasing its metabolism.
Food Interactions
  • Take without regard to meals.
Targets

1. Endothelin-1 receptor

Pharmacological action: yes
Actions: antagonist

Receptor for endothelin-1. Mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system. The rank order of binding affinities for ET-A is:ET1 > ET2 >> ET3

Organism class: human
UniProt ID: P25101 Link_out
Gene: EDNRA Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: antagonist

Non-specific receptor for endothelin 1, 2, and 3. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system

Organism class: human
UniProt ID: P24530 Link_out
Gene: EDNRB 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. 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
Enzymes

1. Cytochrome P450 3A4

Actions: substrate, inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate, inducer

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. 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
Transporters

1. Bile salt export pump

Actions: inhibitor

Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes

UniProt ID: O95342 Link_out
Gene: ABCB11 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 February 08, 2013 16:19