Excretion balance and metabolism of the progestagen Org 30659 in healthy postmenopausal women.
Metabolism of Org 30659 ((17alpha)-17-hydroxy-11-methylene-19-norpregna-4, 15-dien-20-yn-3-one), a new potent progestagen currently under clinical development by NV Organon for use in oral contraception and hormone replacement therapy, was studied in vivo after oral administration to healthy postmenopausal women. After oral administration of [14C]-Org 30659 to postmenopausal women, the compound was extensively metabolized. The dosed radioactivity was predominantly excreted via urine. Org 30659 was to a large extent metabolized at the C3- and the C17-positions. Phase II metabolism, and in particular conjugation with glucuronic acid at the 17beta-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 volunteers, but also metabolism in the A-ring occurred, especially reduction of the 3-keto-Delta(4) moiety to give 3alpha-hydroxy, 5alpha(beta)-dihydro and 3beta-hydroxy, 5alpha-dihydro derivatives. Oxidative metabolism (6beta-hydroxylation) observed in human liver preparations in vitro, was not observed to a significant extent in vivo. So, in vitro human metabolism is different from the in vivo metabolism, indicating that the in vitro-in vivo extrapolation is far from straightforward, at least when only liver preparations are used. The proper choice of the in vitro system (e.g., microsomes, hepatocytes, slices or individually expressed enzymes) and the substrate concentration can be very important determinative factors for the predictability 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 the metabolism of Org 30659 in humans.
Verhoeven
C H
CH
NV Organon, Department of Toxicology and Drug Disposition, Oss, The Netherlands. c.h.verhoeven@organon.sck.akzonobel.nl
Gloudemans
R H
RH
Groothuis
G M
GM
Rietjens
I M
IM
Vos
R M
RM
D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008593:Menopause / Q000378:metabolism* / Q000652:urine; D008875:Middle Aged; D009640:Norethindrone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000652:urine; D045167:Progesterone Congeners / Q000008:administration & dosage / Q000378:metabolism* / Q000652:urine; D051381:Rats; D013045:Species Specificity
D020719:Glucuronides; D045167:Progesterone Congeners; D009640:Norethindrone; C097629:Org 30659