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药品详细

Bosentan(波生坦)

化学结构式图
中文名
波生坦
英文名
Bosentan
分子式
C27H29N5O6S
化学名
4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]benzene-1-sulfonamide
分子量
Average: 551.614
Monoisotopic: 551.183854375
CAS号
147536-97-8
ATC分类
C02K Other Antihypertensives
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

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.

生产厂家
  • Actelion ltd
封装厂家
参考
Synthesis Reference Not Available
General Reference Not Available
剂型
规格
化合物类型
Type small molecule
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
适应症
药理
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.

Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us.

Substrate Enzymes Product
Bosentan
4-(2-Hydroxy1,1-dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-[2,2’]bipyrimidinyl-4-yl]-benzenesulfonamide Details
Bosentan
4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-hydroxyphenoxy)-[2,2’]bipyrimidinyl-4-yl]-benzenesulfonamide Details
Bosentan
    		Ro 48-5053 Details
    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
    理化性质
    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
    药物相互作用
    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.
    食物相互作用
    • Take without regard to meals.

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