ET_A receptor ( Ki = 4.7 nM ); ET_A receptor ( Ki = 95 nM )

Macitentan 30 mg/kg, when administered in addition to Bosentan 100 mg/kg, reduces mean arterial blood pressure (MAP) in hypertensive rats by an additional 19 mm Hg. Bosentan, on the other hand, does not cause an extra MAP decrease when taken in addition to Macitentan. Compared to a maximal effective dose of Bosentan, which is administered on top of Macitentan, there is no additional decrease in mean pulmonary artery pressure (MPAP) in pulmonary hypertensive rats when Macitentan 30 mg/kg is added[3].

The trypan blue exclusion test is used to assess the viability of cells. Bosentan is added to human dermal fibroblasts at the recommended concentrations (10, 20 and 40 μM). After 24 and 48 hours, cell viability is assessed. A hematocytometer is used to count both stained (dead) and unstained (viable) cells[2].

Absorption, Distribution and Excretion
Absolute bioavailability is approximately 50% and food does not affect absorption.
Bosentan is eliminated by biliary excretion following metabolism in the liver.
18 L
4 L/h [patients with pulmonary arterial hypertension]

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Metabolism / Metabolites
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.
Bosentan has known human metabolites that include Hydroxy Bosentan and 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-hydroxyphenoxy)-[2,2-]bipyrimidinyl-4-yl]-benzenesulfonamide.

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Biological Half-Life
Terminal elimination half-life is about 5 hours in healthy adult subjects.

Hepatotoxicity
Bosentan is associated with elevations in serum aminotransferase levels above three times the upper limit of the normal range (ULN) in 3% to 18% of patients, averaging 7.6% using currently recommended doses. The enzyme elevations are usually self-limited and are rarely accompanied by symptoms, but can be more marked and persist and require dose reduction or discontinuation (in 3% to 4% of patients). Monthly monitoring of serum aminotransferase levels is recommended, with discontinuation for levels above 8 times the ULN or for values above 5 times the ULN that persist. There have also been rare reports of clinically apparent liver injury with jaundice associated with bosentan use. The onset of illness was usually within 1 to 6 months of starting bosentan, but cases arising during chronic therapy have also been described (Case 1). The enzyme pattern has typically been hepatocellular or mixed. Immunoallergic features are usually not present and autoantibodies are usually absent or present in low titer. Some cases have been severe and fatalities have been reported, but there have been no published reports of chronic hepatitis or vanishing bile duct syndrome attributed to bosentan. Autoimmune and immunoallergic features are usually not present.
Likelihood score: C (probable cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
A study in one patient taking bosentan during breastfeeding found very low levels in milk. Another woman breastfed her preterm newborn while taking bosentan and sildenafil with no adverse effects reported. Amounts ingested by the infant are far below doses given to treat infants and would not be expected to cause any adverse effects in breastfed infants.
◉ Effects in Breastfed Infants
A 23-year-old woman with congenital heart disease and pulmonary hypertension was treated during pregnancy with bosentan and sildenafil in unspecified dosages. These drugs and warfarin were continued postpartum. Her infant was delivered at 30 weeks by cesarean section and weighed 1.41 kg at birth. She nursed the infant in the neonatal intensive care unit for 11 weeks "with good outcome" according to the authors, but the infant died at 26 weeks from a respiratory syncytial virus infection.[2]
A woman breastfeeding her 21-month-old infant was taking 20 mg of sildenafil 3 times daily and 125 mg of bosentan twice daily to treat pulmonary arterial hypertension. The drugs were begun more than 6 months postpartum. The mother did not report any possible adverse effects, serious health problem or hospitalization of the infant in the period from birth until day 651 postpartum when the infant continued to be partially breastfed.[1]
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Greater than 98% to plasma proteins, mainly albumin.

[1]. Bosentan: a review of its use in the management of mildly symptomatic pulmonary arterial hypertension. Am J Cardiovasc Drugs. 2009;9(5):331-50.

[2]. Bosentan reverses the pro-fibrotic phenotype of systemic sclerosis dermal fibroblasts via increasing DNA binding ability of transcription factor Fli1. Arthritis Res Ther. 2014 Apr 3;16(2):R86.

[3]. Comparison of pharmacological activity of macitentan and bosentan in preclinical models of systemic and pulmonary hypertension. Life Sci. 2014 Nov 24;118(2):333-9.

[4]. Endothelin Regulates Porphyromonas gingivalis-Induced Production of Inflammatory Cytokines. PLoS One. 2016 Dec 28;11(12):e0167713.

Bosentan is a sulfonamide, a member of pyrimidines and a primary alcohol. It has a role as an antihypertensive agent and an endothelin receptor antagonist.
Bosentan is a dual endothelin receptor antagonist marketed under the trade name Tracleer by Actelion Pharmaceuticals. 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.
Bosentan anhydrous is an Endothelin Receptor Antagonist. The mechanism of action of bosentan anhydrous is as an Endothelin Receptor Antagonist, and Cytochrome P450 3A Inducer, and Cytochrome P450 2C9 Inducer.
Bosentan is an endothelin receptor antagonist used in the therapy of pulmonary arterial hypertension (PAH). Bosentan has been associated with serum enzyme elevations during therapy and with rare instances of clinically apparent acute liver injury.
Bosentan is a sulfonamide-derived, competitive and specific endothelin receptor antagonist with a slightly higher affinity for the endothelin A receptor than endothelin B receptor. Bosentan blocks the action of endothelin 1, an extremely potent endogenous vasoconstrictor and bronchoconstrictor, by binding to endothelin A and endothelin B receptors in the endothelium and vascular smooth muscle. Bosentan decreases both pulmonary and systemic vascular resistance and is particularly used in the treatment of pulmonary arterial hypertension.
A sulfonamide and pyrimidine derivative that acts as a dual endothelin receptor antagonist used to manage PULMONARY HYPERTENSION and SYSTEMIC SCLEROSIS.

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Drug 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).
FDA Label
Treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with WHO functional class III. Efficacy has been shown in: , , , Primary (idiopathic and familial) PAH; , PAH secondary to scleroderma without significant interstitial pulmonary disease; , PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger's physiology. , , , Some improvements have also been shown in patients with PAH WHO functional class II. , , Tracleer is also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease. ,
Treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with World Health Organization (WHO) functional class III. Efficacy has been shown in: primary (idiopathic and familial) PAH; PAH secondary to scleroderma without significant interstitial pulmonary disease; PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger's physiology. Some improvements have also been shown in patients with PAH WHO functional class II. Stayveer is also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital-ulcer disease.
Treatment of interstitial pulmonary fibrosis, Treatment of pulmonary arterial hypertension, Treatment of systemic sclerosis

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Mechanism of Action
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. It displays a slightly higher affinity towards ET_A receptors than ET_B receptors. 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.

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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.

C27H29N5O6S

551.61

551.183

C, 58.79; H, 5.30; N, 12.70; O, 17.40; S, 5.81

147536-97-8

Bosentan-d4; 1065472-77-6; Bosentan hydrate; 157212-55-0

104865

White to off-white solid powder

1.3±0.1 g/cm3

742.3±70.0 °C at 760 mmHg

171-175 °C(lit.)

402.8±35.7 °C

0.0±2.6 mmHg at 25°C

1.607

1.15

2

11

11

39

839

0

O=S(NC1=NC(C2=NC=CC=N2)=NC(OCCO)=C1OC3=CC=CC=C3OC)(C4=CC=C(C(C)(C)C)C=C4)=O

GJPICJJJRGTNOD-UHFFFAOYSA-N

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)

4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-ylpyrimidin-4-yl]benzenesulfonamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.75 mg/mL (4.99 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.75 mg/mL (4.99 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.53 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 4: ≥ 2.5 mg/mL (4.53 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 5: ≥ 2.5 mg/mL (4.53 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)