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Titolo:
Excretion balance and metabolism of the progestagen Org 30659 in healthy postmenopausal women
Autore:
Verhoeven, CHJ; Gloudemans, RHM; Groothuis, GMM; Rietjens, IMCM; Vos, RME;
Indirizzi:
NV Organon, Dept Toxicol & Drug Disposit, NL-5340 BH Oss, Netherlands NV Organon Oss Netherlands NL-5340 BH posit, NL-5340 BH Oss, Netherlands Univ Groningen, Univ Ctr Pharm, Inst Drug Explorat, Dept Pharmacokinet & Drug Delivery, Groningen, Netherlands Univ Groningen Groningen Netherlands g Delivery, Groningen, Netherlands Wageningen Univ Agr, Biochem Lab, Wageningen, Netherlands Wageningen Univ Agr Wageningen Netherlands Lab, Wageningen, Netherlands Wageningen Univ Agr, Div Toxicol, Wageningen, Netherlands Wageningen Univ Agr Wageningen Netherlands col, Wageningen, Netherlands
Titolo Testata:
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
fascicolo: 1-2, volume: 73, anno: 2000,
pagine: 39 - 48
SICI:
0960-0760(200005)73:1-2<39:EBAMOT>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN LIVER; IN-VITRO; STEROIDS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
15
Recensione:
Indirizzi per estratti:
Indirizzo: Verhoeven, CHJ NV Organon, Dept Toxicol & Drug Disposit, POB 20, NL-5340 BH Oss, Netherlands NV Organon POB 20 Oss Netherlands NL-5340 BH , Netherlands
Citazione:
C.H.J. Verhoeven et al., "Excretion balance and metabolism of the progestagen Org 30659 in healthy postmenopausal women", J STEROID B, 73(1-2), 2000, pp. 39-48

Abstract

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 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 [C-14]-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 17 beta-hydroxy group, is the major metabolic route for Org 30659 in vivo. Not only phase II metabolismwas 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 3 alpha-hydroxy, 5 alpha(beta)-dihydroand 3 beta-hydroxy, 5 alpha-dihydro derivatives. Oxidative metabolism (6 beta-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. (C) 2000 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 24/09/20 alle ore 07:24:33