In vivo and in vitro disposition profile of tezosentan, an intravenous dual endothelin receptor antagonist, in humans

1. The plasma concentration-time profile of the 14 C-labelled endothelin receptor antagonist tezosentan in healthy male volunteers after a 1-h infusion at 100 mg h − 1 followed a biphasic decline with half-lives of 3-5 min for the initial disposition phase and approximately 4 h for the terminal phase. 2. Tezosentan was predominantly excreted unchanged into faeces, whereas less than 5% of the dose was excreted as unchanged drug in urine. Two isomeric, hydroxylated metabolites (M1, M2) were detected in faeces representing 2-5% of the total radioactivity. 3. In vitro, with human liver microsomes and primary hepatocytes, tezosentan was metabolized at very low rates. Upon prolonged incubation with human hepatocytes for 24 h, formation of the hydroxylated metabolite M1 and a glucuronic acid conjugate, M3, was observed. 4. No relevant inhibition of the human cytochrome P450 (CYP) forms, CYP1A2, 2C9, 2C19, 2D6 and 3A4, was observed in vitro at tezosentan concentrations largely exceeding those observed in clinical trials. 5. In human blood, tezosentan was highly bound to plasma proteins, mainly albumin, and hardly penetrated into red blood cells.