Bosentan, sold under the brand name Tracleer and Safebo among others, is a dual

endothelin receptor antagonist An endothelin receptor antagonist (ERA) is a drug that blocks endothelin receptors. Three main kinds of ERAs exist: * selective ETA receptor antagonists (sitaxentan, ambrisentan, atrasentan, BQ-123, zibotentan, edonentan), which affect endoth ...

medication used in the treatment of pulmonary artery hypertension (PAH). Bosentan is available as film-coated tablets (62.5 mg or 125 mg) or as dispersable tablets for oral suspension (32 mg).

Medical uses

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 Systemic scleroderma, or systemic sclerosis, is an autoimmune rheumatic disease characterised by excessive production and accumulation of collagen, called fibrosis, in the skin and internal organs and by injuries to small arteries. There are two ...

. 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 Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The origina ...

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 Risk Evaluation and Mitigation Strategies (REMS) is a program of the US Food and Drug Administration for the monitoring of medications with a high potential for serious adverse effects. REMS applies only to specific prescription drugs, but can apply ...

(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 Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Signs and symptoms Some of the si ...

, 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.

Adverse effects

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 Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythroc ...

and

hematocrit The hematocrit () (Ht or HCT), also known by several other names, is the volume percentage (vol%) of red blood cells (RBCs) in blood, measured as part of a blood test. The measurement depends on the number and size of red blood cells. It is norm ...

. 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 Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is one of the upper gastrointestinal chronic diseases where stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/ ...

, and diarrhea.

Mechanism of action

Bosentan is a competitive antagonist of

endothelin Endothelins are peptides with receptors and effects in many body organs. Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute ...

-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.

Pharmacokinetics

After oral administration, maximum plasma concentrations of bosentan are attained within 3-5 hours and the terminal elimination half-life (t1/2) is about 5 hours in healthy adult subjects. the exposure to bosentan after intervenous and oral administration is about 2-fold greater in adult patients with pulmonary arterial hypertension than in healthy adult subjects. 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 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules ( xenobiotics), such as toxins or drugs, so that they can be removed from ...

and

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the pro ...

CYP2C19 Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some p ...

may also play a role in its metabolism. It is also a substrate of the hepatic uptake transporter organic anion-transporting polypeptides (

OATP Members of the Organo Anion Transporter (OAT) Family (organic-anion-transporting polypeptides, OATP) are membrane transport proteins or 'transporters' that mediate the transport of mainly organic anions across the cell membrane. Therefore, OATPs a ...

s) 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.

History

Bosentan was studied in

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...

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. It was approved for pulmonary artery hypertension in the US in November 2001, and in the European Union in May 2002.

Society and culture

Economics

By 2013, worldwide sales of bosentan were $1.57 billion. The patents on bosentan started expiring in 2015.

References

External links

* {{Portal bar , Medicine CYP3A4 inducers Endothelin receptor antagonists Orphan drugs Pyrimidines Sulfonamides Catechol ethers Primary alcohols Tert-butyl compounds Diaryl ethers