METABOLISM OF A NEW SYNTHETIC PROGESTAGEN, ORG-2969, BY HUMAN-LIVER INVITRO

The in vitro metabolism of a new synthetic progestagen, Org 2969 (13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-17-ol), was studied in human liver homogenate. The metabolites formed were purified by t.l.c. and identified using capillary g.l.c. and g.l.c.-mass spectrometry of the O-methyl oxime trimethylsilyl ether and trimethylsilyl ether derivatives. Four metabolites, 3α- and 3β-hydroxy-Org 2969, 3-oxo-Org 2969 and 3α-hydroxy-5α-H-Org 2969 were identified. The identification of a fifth metabolite, present in low concentrations, 3-oxo-5α-H-Org 2969 was tentative. On the basis of the results, a scheme for the metabolism of Org 2969 is suggested: Org 2969 is first hydroxylated to 3α/3β-hydroxy-Org 2969, followed by oxidation to 3-oxo-Org 2969, which is further reduced to 3α-hydroxy-5α-H-Org 2969 via 3-oxo-5α-H-Org 2969. Since Org 2969 is only bound relatively weakly by myometrial progesterone receptor, while the affinity of 3-oxo-Org 2969 is high, it has been assumed that at least partly the high biological activity of Org 2969 in vivo is mediated via biotransformation to its 3-oxo derivative. The results of the present investigation indicate the possibility of such a biotransformation in humans. © 1979.