Metabolism of progesterone and synthetic progestational agents.
The metabolism of progesterone, ethinyl-19-nortestosterone, the C-6 and C-17 derivatives of progesterone, and Ro 4-8347 (6-chloro-9beta,10alpha-pregna-1,4,6-triene-3,20-dione) in humans and in liver in vitro is reviewed. Progesterone is reduced at the C-3 and C-20 groups, hydroxylated to polar derivatives at C-6 and C-10, and conjugated almost entirely with glucuronide in human and rabbit liver. The main metabolite is 5beta-pregnane-3alpha,20alpha-diol-glucuronide. The side chain of (21-carbon-14-progesterone is oxydized to C02; 19% was rapidly expired from the lungs, 23% was excreted in urine, and 30% in feces of a pregnant woman. (4-carbon-14-progesterone went into urine (15%-61%) or feces (13%-38%) as glucuronide. Ethinyl-19-nortestosterone is reduced at ring A and hydroxylated at C-10, but the ethinyl side chain is left intact. C-6 and C-17 progesterone derivatives such as megestrol acetate have proved to be resistant to liver metabolizing enzymes in vitro. The retro-steroids, with a C-9 beta hydrogen and C-10 alpha methyl, are only metabolized to 20alpha derivatives. Ro 4-8347 resisted metabolism to the 5beta form in humans or rats in vivo or in vitro. In human liver its main metabolite was the 20alpha-hydroxy derivative, but in rat urine it was a 16alpha-hydroxy derivative.