Bosentan

Absorption

Absolute bioavailability is approximately 50% and food does not affect absorption.

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.

Description

Bosentan was introduced in the US as a twice-daily oral treatment for pulmonary arterial hypertension. It can be synthesized in five steps via condensation of diethyl (2- methoxyphenoxy)malonate with pyrimidine-2-carboxamidine to give the precursor of the symmetrical central dichloropyrimidine ring which is then successively treated with the potassium salt of 4-tert-butylbenzenesulfonamide and the sodium salt of ethylene gycol. Bosentan is the first endothelin (ET) receptor antagonist to be launched. ET-1, the most potent endogenous vasoconstrictor known, has been demonstrated to play a major role in the functional and structural changes observed in pulmonary hypertension. Bosentan is a mixed ET_A and ET_B receptor antagonist that inhibits the pulmonary arterial vasoconstricting effect of ET-1 predominantly mediated via ET_A receptors on smooth muscle cells. In a hypoxia-induced model of pulmonary hypertension in rat, it reduced the development of pulmonary hypertension as well as right ventricular hypertrophy and prevented pulmonary arterial remodeling. In clinical trials, patients treated with bosentan showed a 20% increase in exercise capacity compared to placebo as measured by the six minute walk test. Bosentan not only improved the distance walked by patients but also significantly decreased mean pulmonary artery pressure, mean pulmonary vascular resistance, mean capillary wedge pressure and mean right atrial pressure. It demonstrated a beneficial selectivity for the pulmonary vasculature since it had no significant effect on mean aortic blood pressure and systolic vascular resistance. The compound is hepatically metabolized into three major metabolites by CYP3A4 and 2C9 and almost exclusively eliminated in the bile. Although large interspecies differences in systemic plasma clearance was observed (1.5 mL/min/kg in dogs to 72 mL/min/kg in rabbits), a satisfactory systemic clearance (2 mL/min/kg) was measured in human. The most frequent adverse effect was reversible elevation of liver transaminases. This adverse reaction appears to be due to intracellular accumulation of cytotoxic bile salts resulting from inhibition of the hepatocanalicular bile salt export pump by bosentan.

The Uses of Bosentan

Bosentan is a mixed endothelin receptor antagonist. Used as a vasodilator. Antihypertensive.

Background

Bosentan is a dual endothelin receptor antagonist marketed under the trade name Tracleer by Actelion Pharmaceuticals. Bosentan is used to treat pulmonary hypertension by blocking the action of endothelin molecules that would otherwise promote narrowing of the blood vessels and lead to high blood pressure.

Indications

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).

What are the applications of Application

Bosentan is a mixed endothelin receptor antagonist

Pharmacokinetics

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.

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.