Identification and anti-androgenic activity of the metabolites of 17.ALPHA.-acetoxy-6-chloropregna-4,6-diene-3,20-dione (chlormadinone acetate) in the rat, rabbit, dog and man.

Abstract

The metabolic fate of chlormadinone acetate (CMA), which is a new anti-androgenic agent, has been investigated with rats, rabbits, dogs and humans. Fourteen unconjugated metabolites and three conjugated metabolites were isolated from urine, feces and bile after oral administration of CMA. The structures of these metabolites were deduced from physico-chemical data and definitely characterized by direct comparison with the authentic samples (see Chart 1). There was a marked species difference in the metabolic pattern. Especially, configuration of 2-hydroxy group in the 2-hydroxylated metabolites was different among species. Further, the occurrence of 1-hydroxylation and 15-hydroxylation, new metabolic pathways in steroidal agents, was found in the rats and humans. The anti-androgenic activities of the metabolites were listed in Table III. 3β-Hydroxy CMA, one of the main metabolites in humans and rats, and its acetate were 0.7 time as active as CMA, whereas other main metabolites, 2α, 3β-dihydroxy CMA and 2α-acetoxy CMA, were not effective.