Indications
Bosentan is prescribed for the management of pulmonary arterial hypertension (PAH), specifically in patients presenting with WHO functional class III or IV symptoms. The primary goals of Bosentan therapy are to enhance exercise capacity and to mitigate the progression of clinical symptoms, thereby improving overall patient outcomes.
Pharmacodynamics
Classified as an endothelin receptor antagonist (ERA), Bosentan counteracts the harmful effects of elevated endothelin levels found in PAH patients. Endothelin is a powerful vasoconstrictor present in increased concentrations within the plasma and lung tissue of these patients. Bosentan impedes endothelin from binding to its receptors, effectively reducing its vasoconstrictive impact and helping to manage PAH symptoms.
Absorption
The drug exhibits an absolute bioavailability of approximately 50%, indicating that half of the administered dose reaches systemic circulation intact. Importantly, the absorption of Bosentan is unaffected by food intake, which allows for flexibility in dosing without regard to meals.
Metabolism
Bosentan undergoes metabolism primarily in the liver, facilitated by cytochrome P450 enzymes, specifically CYP2C9 and CYP3A4, and possibly CYP2C19. This process yields three metabolites, one of which, Ro 48-5033, retains pharmacological activity. The active metabolite is estimated to contribute 10% to 20% to the overall pharmacological activity of Bosentan, suggesting it plays a supportive role in the drug's efficacy.
Mechanism of Action
Bosentan functions as a dual antagonist targeting endothelin receptors, particularly ETA and ETB subtypes. Endothelin-1 (ET-1), a potent neurohormone, exerts its physiological effects by binding to these receptors located on endothelial cells and vascular smooth muscle. It holds a marginally higher binding affinity for ETA receptors over ETB receptors. Elevated levels of ET-1 are observed in the plasma and lung tissues of individuals suffering from pulmonary arterial hypertension, indicating its contributory role in the pathogenesis of this condition. By competitively inhibiting ET-1 at these receptor sites, Bosentan mitigates its harmful effects, thereby offering therapeutic benefits to patients with this ailment.
