|Trade names||Tracleer, Stayveer|
|Drug class||Endothelin receptor antagonist|
|Main uses||Pulmonary artery hypertension (PAH), systemic sclerosis|
|Side effects||Respiratory tract infection, low red blood cells, fever|
|Elimination half-life||5 hours|
|Chemical and physical data|
|Molar mass||551.62 g·mol−1|
|3D model (JSmol)|
Bosentan, sold under the brand name Tracleer among others, is a medication used to treat pulmonary artery hypertension (PAH) and systemic sclerosis. It is taken by mouth. It may be used in those over the age of 2.
Common side effects include respiratory tract infection, low red blood cells, and fever. Other side effects may include swelling, liver probelms, and pulmonary veno-occlusive disease. Use in pregnancy may harm the baby. It is a endothelin receptor antagonist.
Bosentan was approved for medical use in the United States in 2001 and Europe in 2022. It is avaliable as a generic medication. In the United Kingdom 4 weeks of treatment costs about £110 as of 2021. This amount in the United States is about 1,100 USD.
Bosentan is used to treat people with moderate pulmonary arterial hypertension and to reduce the number of digital ulcers — open wounds on especially on fingertips and less commonly the knuckles — in people with systemic scleroderma.
Bosentan causes harm to fetuses and pregnant women must not take it, and women must not become pregnant while taking it (Pregnancy Category X). It may render hormonal contraceptives ineffective so other forms of birth control must be used.
In the US it is only available from doctors who follow an FDA-mandated risk evaluation and mitigation strategy (REMS) with respect to risks to fetuses and its risks of causing liver damage. The doctor must document a negative pregnancy test for women before prescribing the drug, counsel about contraception, and give regular pregnancy tests. Because there is a high risk that bosentan causes liver damage, the REMS plan also requires pre-testing for elevated transaminases and regular testing while the drug is being taken. Bosentan is also contraindicated in patients taking glyburide due to an increased risk of increased liver enzymes and liver damage when these two agents are taken together.
Bosentan is available as film-coated tablets (62.5 mg or 125 mg) or as dispersable tablets for oral suspension (32 mg). It is started at 62.5 mg twice per day for 4 weeks and than increased to 125 mg twice per day.
In addition to the risk of causing birth defects and of causing liver damage, bosentan has a high risk of causing edema, pulmonary veno-occlusive disease, decreasing sperm counts, and decreases in hemoglobin and hematocrit.
Very common adverse effects (occurring in more than 10% of people) include headache, elevated transaminases, and edema. Common adverse effects (between 1% and 10% of people) include anemia, reduced hemoglobin, hypersensitivity reactions, skin inflammation, itchiness, rashes, red skin, flushing, fainting, heart palpitations, low blood pressure, nasal congestion, gastro-esophageal reflux disease, and diarrhea.
Mechanism of action
Bosentan is a competitive antagonist of endothelin-1 at the endothelin-A (ET-A) and endothelin-B (ET-B) receptors. Under normal conditions, endothelin-1 binding of ET-A receptors causes constriction of the pulmonary blood vessels. Conversely, binding of endothelin-1 to ET-B receptors has been associated with both vasodilation and vasoconstriction of vascular smooth muscle, depending on the ET-B subtype (ET-B1 or ET-B2) and tissue. Bosentan blocks both ET-A and ET-B receptors, but is thought to exert a greater effect on ET-A receptors, causing a total decrease in pulmonary vascular resistance.
Absolute bioavailability of bosentan is about 50% in healthy subjects. Peak plasma concentration of bosentan with the dispersable tablets for oral suspension is 14% less on average compared to peak concentration of the oral tablets.
Bosentan is a substrate of CYP3A4 and CYP2C9. CYP2C19 may also play a role in its metabolism. It is also a substrate of the hepatic uptake transporter organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, and OATP2B1.
Elimination of bosentan is mostly hepatic, with minimal contribution from renal and fecal excretion.
Use of bosentan with cyclosporine is contraindicated because cyclosporine A has been shown to markedly increase serum concentration of bosentan.
Bosentan was studied in heart failure in a trial called REACH-1 that was terminated early in 1997, due to toxicity at the dose that was being studied; as of 2001, the results of that trial had not been published.
Society and culture
By 2013, worldwide sales of bosentan were $1.57 billion. The patents on bosentan started expiring in 2015.
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