Excretion balance and metabolism of the progestagen Org 30659 in healthy postmenopausal women

Metabolism of Org 30659 ((17 alpha)-17-hydroxy-11-methylene-19-norpregna-4, 15-dien-20-yn-3-one), a new potent progestagen currently under clinical dev elopment by NV Organon for use in oral contraception and hormone replacemen t therapy was studied in vivo after oral administration to healthy postmeno pausal women. After oral administration of [C-14]-Org 30659 to postmenopaus al women, the compound was extensively metabolized. The dosed radioactivity was predominantly excreted via urine. Org 30659 was to a large extent meta bolized at the C3- and the C17-positions. Phase II metabolism, and in parti cular conjugation with glucuronic acid at the 17 beta-hydroxy group, is the major metabolic route for Org 30659 in vivo. Not only phase II metabolism was observed for Org 30659 after oral administration to postmenopausal volu nteers, but also metabolism in the A-ring occurred, especially reduction of the 3-keto-Delta(4) moiety to give 3 alpha-hydroxy, 5 alpha(beta)-dihydro and 3 beta-hydroxy, 5 alpha-dihydro derivatives. Oxidative metabolism (6 be ta-hydroxylation) observed in human liver preparations in vitro, was not ob served to a significant extent in vivo. So, in vitro human metabolism is di fferent from the in vivo metabolism, indicating that the in vitro-in vivo e xtrapolation is far from straightforward, at least when only liver preparat ions are used. The proper choice of the in vitro system (e.g., microsomes, hepatocytes, slices or individually expressed enzymes) and the substrate co ncentration can be very important determinative factors for the predictabil ity of the in vitro system for the in vivo situation. Species comparison of the metabolic routes of Org 30659 after oral administration indicated that the monkey seems to be a better representative species than the rat for th e metabolism of Org 30659 in humans. (C) 2000 Elsevier Science Ltd. All rig hts reserved.