| 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). |
| 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. |
| Mechanism of action |
Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ETA and ETB
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 ETA and ETB. Bosentan has a slightly higher affinity for ETA receptors than for ETB receptors. |
| Absorption |
Absolute bioavailability is approximately 50% and food does not affect absorption. |
| Volume of distribution |
|
| 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]
|
| Toxicity |
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. |
