IN-VITRO AND IN-VIVO METABOLISM OF THE PROGESTAGEN ORG-30659 IN SEVERAL SPECIES

The metabolism of Org 30659 [(17 -11-methylene-19-norpregna-4,15-dien- 20-yn-3-one], a new potent progestagen currently under clinical develo pment by NV Organon for use in oral contraceptive and hormone replacem ent therapy, was studied in vivo after oral administration to rats and monkeys and in vitro using rat, rabbit, monkey, and human liver micro somes and rat and human hepatocytes. After oral administration of [7-H -3]Org 30659 to rats and monkeys, Org 30659 was extensively metabolize d in both species. Fecal excretion appeared to be the main route of el imination. In rats, opening of the A-ring, resulting in a 2-OH,4-carbo xylic acid, 5 alpha-H metabolite of Org 30659, was the major metabolic route in vivo. Other metabolic routes involved the introduction of an OH group at C15 beta, followed by a shift of the Delta(15)-double bon d to a 16/17-double bond with subsequent removal of the OH group at C1 7 and reduction of the 3-keto,Delta(4) moiety followed by sulfate conj ugation of the 3-OH substituent. These metabolic routes observed in vi vo were also major routes in incubations with rat hepatocytes. In rat liver microsomes, Org 30659 was metabolized by reduction of the 3-keto ,Delta(4) moiety. Rat hepatocyte incubations with Org 30659 were more representative of the in vivo metabolism of Org 30659, compared with r at microsomal incubations. Both in vitro and in vivo, the majority of the metabolites were 3 alpha-OH,4,5 alpha-dihydro derivatives. In monk eys, Org 30659 was mainly metabolized at the C3- and C17-positions in vivo. The 3-keto moiety was reduced to both 3 beta-OH and 3 alpha-OH s ubstituents. In addition to phase I metabolites, glucuronic acid conju gates were observed in vivo. In monkey liver microsomes, the 6 beta-OH metabolite of Org 30659 was the major metabolite present. Similar to the monkey liver microsomes, rabbit and human liver microsomes convert ed Org 30659 to the 6 beta-OH metabolite. This metabolite was also the major metabolite in incubations with human hepatocytes.