The disposition and metabolism of zibotentan (ZD4054): an oral-specific endothelin A receptor antagonist in mice, rats and dogs

1. Zibotentan (ZD4054) is an oral-specific endothelin A receptor antagonist in development for the treatment of castration-resistant prostate cancer. 2. In a number of preclinical studies, the disposition and metabolism of zibotentan were investigated in mice, rats and dogs. 3. Following oral and intravenous administration, zibotentan was slowly absorbed (maximal concentration at approximately 4 h) and rapidly excreted, with the majority being eliminated by 48 h. The main route of elimination was via the urine in dogs and female rats, but via the faeces in male rats and mice of both sexes. Zibotentan was moderately bound to plasma proteins of all species examined (55-95%), and widely distributed throughout all tissues with the highest concentrations seen in the organs of excretion. Zibotentan was moderately metabolised. 4. Zibotentan was well absorbed, moderately bound to plasma proteins, widely distributed and excreted predominantly via the urine.