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.[4][3][6]
Bosentan is contraindicated in people taking glyburide due to an increased risk of increased liver enzymes and liver damage when these two agents are taken together.[4]
Use of bosentan with cyclosporine is contraindicated because cyclosporine A has been shown to markedly increase serum concentration of bosentan.[4]
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.[7]
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.[4][3]
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.[8] 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.[9] 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.[4]
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.[10]
Absolute bioavailability of bosentan is about 50% in healthy subjects.[11] 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.[4]
Bosentan is a substrate of CYP3A4 and CYP2C9. CYP2C19 may also play a role in its metabolism.[4] It is also a substrate of the hepatic uptake transporter organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, and OATP2B1.[12][13]
Elimination of bosentan is mostly hepatic, with minimal contribution from renal and fecal excretion.[14]
Use of bosentan with cyclosporine is contraindicated because cyclosporine A has been shown to markedly increase serum concentration of bosentan.[4]
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. [15]
It was approved for pulmonary artery hypertension in the US in November 2001,[4][16] and in the European Union in May 2002.[3][5]
^Weber C, Schmitt R, Birnboeck H, Hopfgartner G, van Marle SP, Peeters PA, et al. (August 1996). "Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects". Clinical Pharmacology and Therapeutics. 60 (2): 124–37. doi:10.1016/S0009-9236(96)90127-7. PMID8823230. S2CID3039181.
^Jones HM, Barton HA, Lai Y, Bi YA, Kimoto E, Kempshall S, et al. (May 2012). "Mechanistic pharmacokinetic modeling for the prediction of transporter-mediated disposition in humans from sandwich culture human hepatocyte data". Drug Metabolism and Disposition. 40 (5): 1007–17. doi:10.1124/dmd.111.042994. PMID22344703. S2CID15463540.
^Treiber A, Schneiter R, Häusler S, Stieger B (August 2007). "Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil". Drug Metabolism and Disposition. 35 (8): 1400–7. doi:10.1124/dmd.106.013615. PMID17496208. S2CID2625368.
^Weber C, Gasser R, Hopfgartner G (July 1999). "Absorption, excretion, and metabolism of the endothelin receptor antagonist bosentan in healthy male subjects". Drug Metabolism and Disposition. 27 (7): 810–5. PMID10383925.
^Packer M, McMurray J, Massie BM, Caspi A, Charlon V, Cohen-Solal A, et al. (February 2005). "Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study". Journal of Cardiac Failure. 11 (1): 12–20. doi:10.1016/j.cardfail.2004.05.006. PMID15704058.
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