Macitentan (Opsumit)

An endothelin receptor antagonist (ERA) indicated for treatment of pulmonary hypertension to delay disease progression.

Trade name Opsumit

Oral agent.

Metabolism by hydrolysis, and oxidation by CYP3A4 enzymes.

Excretion is two-third in urine and one third in feces.

An endothelin receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH).

It is a dual ERA, meaning that it acts as an antagonist of two endothelin (ET) receptor subtypes, ETA and ETB.

Has a 50-fold increased selectivity for the ETA subtype compared to the ETB subtype.

Endothelin (ET) is a potent blood vessel constricting substance that is secreted by endothelial cells.

The most common ET form released in the lung is ET-1.

Upon release, ET-1 binds to the ET receptors that are expressed on arterial smooth muscle cells and fibroblasts in the lungs.

Endothelin receptors are G protein coupled receptors and, when activated, lead to an increase in intracellular calcium levels via the Gαq signaling pathway.

The rise in intracellular calcium leads to contraction of the arterial smooth muscle, as well as vascular remodelling due to cell proliferation.

Prolonged constriction and fibrosis are factors in the pathogenesis of PAH.

This drug blocks the ET1-dependent rise in intracellular calcium by inhibiting the binding of ET-1 to ET receptors.

Blocking of the ETA receptor subtype is more important in the treatment of PAH than blocking of ETB, as there are higher numbers of ETA receptors than ETB receptors in pulmonary arterial smooth muscle cells.

Treatment at 10 mg oral dose once a day.

Its half-life is about 16 hours.

Reaches steady state by the third day of administration, as it absorbed slowly.

Has an active metabolite which reaches its peak plasma concentration about 30 hours after the first dose is administered, and has a half-life of approximately 48 hours.

Both compounds can be excreted from the body through the urine or feces.

Drug mainly metabolized via the liver enzyme CYP3A4.

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