Metabolism of Casodex in laboratory animals

Abstract

1. Casodex, a non-steroidal antiandrogen, was eliminated primarily in faeces by rat, mouse, rabbit and dog. Rat, mouse and rabbit eliminated 20–30% of a single oral dose (8–25 mg/kg) in urine; only 3–4% was excreted in urine by dog (2–5 mg/kg). Oral absorption was about 80% in rat, mouse, rabbit and dog.

2. Most of the dose was recovered in 48 h from rat, mouse and rabbit. In rat, < 1% of the dose was exhaled as ¹⁴CO₂ and < 1% remained in the carcass after 7 days. Recovery from dog was incomplete in 4 days but consistent with the long plasma elimination half-life of 7–7–5 days. Casodex was eliminated from rat plasma with a half-life of 17–21 h.

3. Examination of urine indicated extensive metabolism of Casodex and showed a marked species difference. In rat, mouse and dog, Casodex was cleaved at the amide to yield a carboxylic acid and an aromatic amine which subsequently underwent ring hydroxylation with sulphate conjugation. In rabbit, the major urinary metabolite was Casodex glucuronide, conjugated on the tertiary hydroxyl.

4. The major component in faeces of all species was unchanged Casodex; some hydroxy-Casodex was also observed in rat faeces. Analysis of rat and dog bile indicated that Casodex and hydroxy-Casodex were eliminated in bile primarily as glucuronide conjugates.