Ambrisentan

Endothelin-1 (ET-1) is a powerful peptide that acts on the cells that make it and on the cells next to them. It works through two receptor types, ETA and ETB, found in vascular smooth muscle and the endothelium. ETA mainly causes vasoconstriction and cell proliferation, whereas ETB mainly causes vasodilation, slows cell proliferation, and clears ET-1 from the body.

Ambrisentan blocks the ETA receptor with high affinity. It is far more selective for ETA than for ETB (more than 4000-fold). What this high selectivity means in clinical practice is not yet known.

In healthy people, the pharmacokinetics of Ambrisentan (S-Ambrisentan) are dose proportional. Its absolute bioavailability is not known. After an oral dose, Ambrisentan is absorbed and reaches peak concentration in about 2 hours, in both healthy subjects and PAH patients. Food does not change how much of the medicine is absorbed. Laboratory studies show that Ambrisentan is a substrate of P-gp. About 99% of it binds to plasma proteins.

Ambrisentan is removed from the body mainly through non-renal routes. How much is broken down by metabolism compared with eliminated through bile has not been well studied. In plasma, the AUC of 4-hydroxymethyl Ambrisentan is about 4% of the AUC of the parent Ambrisentan. In the body, S-Ambrisentan converts to R-Ambrisentan only to a negligible extent.

The mean oral clearance of Ambrisentan is 38 mL/min in healthy subjects and 19 mL/min in PAH patients. Its terminal half-life is 15 hours. Even so, at steady state the mean trough concentration is about 15% of the mean peak concentration, and after long-term daily dosing the accumulation factor is about 1.2. This means the effective half-life of Ambrisentan is about 9 hours.