[CAS NO. 177036-94-1]  Ambrisentan

Ambrisentan only increases intracellular calcein fluorescence in P388/dx cells at concentrations above 100 μM and in L-MDR1 cells not at all indicating negligible P-gp inhibition. Ambrisentan inhibits specific [(125)I]ET-1 binding in these tissues in a concentration-dependent manner. Ambrisentan undergoes oxidative metabolism mainly by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP3A5 and CYP2C19. Ambrisentan is not only a strong inducer of CYP3A4, but also of ABCB1 and ABCG2. Ambrisentan also has a concentration-dependent effect on PXR activity, but because plateau effects are not reached, an EC50-value could not be calculated. Ambrisentan inhibits specific [(125)I]ET-1 binding in a concentration-dependent manner at nanomolar ranges of IC50. Ambrisentan significantly increases the dissociation constant for bladder [(125)I]ET-1 binding without affecting maximal number of binding sites (Bmax). Ambrisentan seem to bind to bladder ET-1 receptor in a competitive and reversible manner. Ambrisentan is an effective and safe treatment which is a valuable addition to the armamentarium against PAH. Ambrisentan offers a relative lack of drug interactions, once daily dosing and reassuring liver safety, offering safety and convenience advantages over bosentan.