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

Zibotentan (ZD4054) is an oral-specific endothelin A receptor antagonist in development for the treatment of castration-resistant prostate cancer. In a number of preclinical studies, the disposition and metabolism of zibotentan were investigated in mice, rats and dogs. Following oral and intravenous...

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Bibliographic Details
Published in:Xenobiotica 2011-09, Vol.41 (9), p.784-796
Main Authors: Clarkson-Jones, J.A., Kenyon, A.S.J., Tomkinson, H.K.
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Biotransformation
Blood Proteins - metabolism
Chromatography, High Pressure Liquid
Dogs
Endothelin A Receptor Antagonists
Female
Male
metabolites
Mice
pharmacokinetics
Protein Binding
Pyrrolidines - administration & dosage
Pyrrolidines - blood
Pyrrolidines - metabolism
Pyrrolidines - pharmacokinetics
Radioactivity
Rats
Receptor, Endothelin A - metabolism
Tissue Distribution
ZD4054
zibotentan
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Summary:Zibotentan (ZD4054) is an oral-specific endothelin A receptor antagonist in development for the treatment of castration-resistant prostate cancer. In a number of preclinical studies, the disposition and metabolism of zibotentan were investigated in mice, rats and dogs. 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. Zibotentan was well absorbed, moderately bound to plasma proteins, widely distributed and excreted predominantly via the urine.
ISSN:0049-8254
1366-5928
DOI:10.3109/00498254.2011.562565