Ludaterone acetate

The metabolic fate of osaterone acetate (TZP-4238), a new antiandrogenic agent, has been studied in mice, rats, dogs, and humans.Fifteen metabolites were isolated from urine, bile and feces of animals and humans following oral administration of ¹⁴C-labeled and nonlabeled drug.The structures of those metabolites were identified by comparison of their chromatog. and spectral data with the data of authentic samples.The main urinary and plasma metabolites were 17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnadiene-3,20-dione (PB-1) and 17α-acetoxy-6-chloro-21-hydroxy-2-oxa-4,6-pregnadiene-3,20-dione (PB-2) in rats, dogs and humans, whereas the plasma main metabolite in mice was 11β-OH TZP-4238.The biliary main metabolite was PB-1 in rats.Administered to dogs, TZP-4238 was metabolized through three courses: oxidation at C-15, C-11, C-1 and C-21 Me group; hydrolysis of the 17α-acetyl group; and dechlorination at C-6.There was a marked species difference in the metabolic pattern.Especially, 11-hydroxylated metabolites were found in the plasma and urine of dogs and mice, but there was no evidence of its presence in human urine or plasma.In rat plasma the compound was present in mere trace amountsIn addition, rats showed a sex difference in the plasma metabolites although dogs and mice showed no significance sex difference.One of the main metabolites, PB-1, was twice as active as the parent compound, whereas another metabolite 11-OH TZP-4238, was nearly as active as cortisol in affinity of cortisol for the corticoid receptor.