In vitro and in vivo metabolism of desogestrel in several species.

The metabolism of desogestrel (13-ethyl-11-methylene-18, 19-dinor-17alpha-pregn-4-en-20-yn-17-ol), an orally active progestogen, was studied in vivo after administration of single oral doses to rats and dogs and in vitro using rat, rabbit, dog, and human liver microsomes. Metabolites were isolated and identified by NMR and MS analysis. After oral administration of [3H]desogestrel to rats and dogs, desogestrel was extensively metabolized in both species. Radioactivity was predominantly eliminated in the feces. In rats, desogestrel was metabolized mainly at the C3-, C5-, C11-, and C15-positions. Both in vivo and in vitro, the majority of metabolites were 3alpha-hydroxy,4,5alpha-dihydro derivatives. Other main metabolic routes for desogestrel in rats were 15alpha-hydroxylation and epoxidation of the C11-methylene moiety. In addition to phase I metabolites, glucuronic acid and sulfate conjugates of desogestrel were observed in vivo. In dogs, desogestrel was mainly metabolized at the C3- and C17-positions. In contrast to the rat metabolites, metabolites isolated from dog urine or feces were mainly 3beta-hydroxy,4,5alpha-dihydro derivatives. In most of the metabolites present in dog urine and feces, the five-membered D-ring was expanded to a six-membered D-ring, i.e. D-homoannulation to a 17A-keto-D-homo ring. D-Homo metabolites, which were major metabolites in plasma, urine, and feces of dogs, were not observed in vitro. In dog liver microsomes, the 3-keto metabolite of desogestrel was the major metabolite. Similarly to dog liver microsomes, rabbit and human liver microsomes mainly converted desogestrel to its 3-keto metabolite. Predominant positions for further hydroxylation of the 3-keto metabolite of desogestrel were the C6-position (6beta-hydroxy) and the ethyl substituent at the C13-position, for both species.