Bosentan

Các tên gọi khác (4 ) :

4-(1,1-Dimethylethyl)-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-(2,2'-bipyrimidin)-4-yl) benzenesulfornamide
Bosentan hydrate
Bosentanum
P-Tert-butyl-N-(6-(2-hydroxyethoxy)-5-(O-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl)benzenesulfonamide

antihypertensive agents

Thuốc Gốc

Small Molecule

CAS: 147536-97-8

ATC: C02KX01

ĐG : Actelion Pharmaceuticals Inc. , http://www.actelion.com

CTHH: C₂₇H₂₉N₅O₆S

PTK: 551.614

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.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₂₇H₂₉N₅O₆S

Phân tử khối

551.614

Monoisotopic mass

551.183854375

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)

InChI Key

InChIKey=GJPICJJJRGTNOD-UHFFFAOYSA-N

IUPAC Name

4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]benzene-1-sulfonamide

Traditional IUPAC Name

bosentan

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

Độ hòa tan

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).

logP

3.7

logS

-4.8

pKa (strongest acidic)

5.8

pKa (Strongest Basic)

-0.43

PSA

145.65 Å²

Refractivity

166.66 m³·mol^-1

Polarizability

57.89 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

-1

Number of Rings

Bioavailability

MDDR-Like Rule

true

caco2 Permeability

-5.98

Dược Lực Học : 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.

Cơ Chế Tác Dụng : 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. Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ET_A and ET_B 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 ET_A and ET_B. Bosentan has a slightly higher affinity for ET_A receptors than for ET_B receptors.

Dược Động Học :

▧ 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]

Độc Tính : 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.

Chỉ Định : 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).

Tương Tác Thuốc :

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.
Dicoumarol 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 Acetate 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.

Liều Lượng & Cách Dùng : Tablet, film coated - Oral - 125 mg
Tablet, film coated - Oral - 62.5 mg

Dữ Kiện Thương Mại

Nhà Sản Xuất

Công ty : Actelion

Sản phẩm biệt dược : Tracleer

Đóng gói

Công ty : Actelion Pharmaceuticals Inc.

Website : http://www.actelion.com
Công ty : Action Pharmaceuticals Ltd.
Công ty : Haupt Pharma

Website : http://haupt-pharma.de
Công ty : Patheon Inc.

Website : http://www.patheon.com

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB00559

PubChem Compound

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=104865

PubChem Substance

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=46507154

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D01227

ChemSpider

http://www.chemspider.com/Chemical-Structure.94651.html

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/66215-101-06

PharmGKB

http://www.pharmgkb.org/drug/PA10034

Wikipedia

http://en.wikipedia.org/wiki/Bosentan

RxList

http://www.rxlist.com/cgi/generic3/tracleer.htm

Drugs.com

http://www.drugs.com/cdi/bosentan.html

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