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Titolo:
IN-VITRO AND IN-VIVO METABOLISM OF THE PROGESTAGEN ORG-30659 IN SEVERAL SPECIES
Autore:
VERHOEVEN CHJ; KREBBERS SFM; WAGENAARS GN; BOGY CJ; GROOTHUIS GMM; OLINGA P; VOS RME;
Indirizzi:
NV ORGANON,DEPT TOXICOL & DRUG DISPOSIT,POB 20 NL-5340 BH OSS NETHERLANDS NV ORGANON,ANALYT CHEM DEV NL-5340 BH OSS NETHERLANDS GRONINGEN INST DRUG STUDIES,UNIV CTR PHARM,DEPT PHARMACOKINET & DRUG DELIVERY GRONINGEN NETHERLANDS
Titolo Testata:
Drug metabolism and disposition
fascicolo: 11, volume: 26, anno: 1998,
pagine: 1102 - 1112
SICI:
0090-9556(1998)26:11<1102:IAIMOT>2.0.ZU;2-8
Fonte:
ISI
Lingua:
ENG
Soggetto:
OXIDATION; ENZYME;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
22
Recensione:
Indirizzi per estratti:
Citazione:
C.H.J. Verhoeven et al., "IN-VITRO AND IN-VIVO METABOLISM OF THE PROGESTAGEN ORG-30659 IN SEVERAL SPECIES", Drug metabolism and disposition, 26(11), 1998, pp. 1102-1112

Abstract

The metabolism of Org 30659 [(17 -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 contraceptive and hormone replacement therapy, was studied in vivo after oral administration to rats and monkeys and in vitro using rat, rabbit, monkey, and human liver microsomes and rat and human hepatocytes. After oral administration of [7-H-3]Org 30659 to rats and monkeys, Org 30659 was extensively metabolized in both species. Fecal excretion appeared to be the main route of elimination. In rats, opening of the A-ring, resulting in a 2-OH,4-carboxylic 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 bond to a 16/17-double bond with subsequent removal of the OH group at C17 and reduction of the 3-keto,Delta(4) moiety followed by sulfate conjugation of the 3-OH substituent. These metabolic routes observed in vivo were also major routes in incubations with rat hepatocytes. In ratliver microsomes, Org 30659 was metabolized by reduction of the 3-keto,Delta(4) moiety. Rat hepatocyte incubations with Org 30659 were morerepresentative of the in vivo metabolism of Org 30659, compared with rat microsomal incubations. Both in vitro and in vivo, the majority ofthe metabolites were 3 alpha-OH,4,5 alpha-dihydro derivatives. In monkeys, Org 30659 was mainly metabolized at the C3- and C17-positions invivo. The 3-keto moiety was reduced to both 3 beta-OH and 3 alpha-OH substituents. In addition to phase I metabolites, glucuronic acid conjugates were observed in vivo. In monkey liver microsomes, the 6 beta-OH metabolite of Org 30659 was the major metabolite present. Similar tothe monkey liver microsomes, rabbit and human liver microsomes converted Org 30659 to the 6 beta-OH metabolite. This metabolite was also the major metabolite in incubations with human hepatocytes.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 12/07/20 alle ore 05:24:17