Macitentan is a new dual ETA/ETB endothelin (ET) receptor antagonist, with mean IC50 values of 0.5 ± 0.2 nM (n= 17) to inhibit the binding of 125I-ET-1 to recombinant ETA receptors, and of 391±182 nM (n= 17) for ETB receptors in Chinese hamster ovary cells [1].

ETA and ETB are ET receptors, both of them mediate the detrimental actions of ET-1, and dual blockade of them may be necessary [1].

In microsomal membranes of human-ETA and ETB-overexpressing Chinese hamster ovary cells, macitentan inhibited the binding between 125I-ET-1 and recombinant ETA receptors, with a mean IC50 value of 0.5 ± 0.2 nM (n= 17). The mean IC50 value for ETB receptors was 391±182 nM (n= 17). Macitentan completely inhibited the effect that ET-1 increased intracellular calcium in non-recombinant cells [1].

Intravenous administrated macitentan had a volume of distribution largely exceeding plasma volume and a terminal half-life of 2 h in rats. Macitentan was hence metabolized to its major and the only circulating metabolite, a dual ET receptor antagonist, ACT-132577. ACT-132577 also had a volume of distribution greater than the plasma volume. It showed a longer half-life than macitentan in rats. In rat, multiple oral dosing of macitentan at a dose of 10 mg/kg led to 4 to 5-fold higher exposure levels of ACT-132577 than those of the parent compound [1].