In vitro and in vivo metabolism of the progestagen Org 30659 in several species.
The 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 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 [7-3H]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, 5alpha-H metabolite of Org 30659, was the major metabolic route in vivo. Other metabolic routes involved the introduction of an OH group at C15beta, followed by a shift of the Delta15-double bond to a 16/17-double bond with subsequent removal of the OH group at C17 and reduction of the 3-keto,Delta4 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 rat liver microsomes, Org 30659 was metabolized by reduction of the 3-keto,Delta4 moiety. Rat hepatocyte incubations with Org 30659 were more representative of the in vivo metabolism of Org 30659, compared with rat microsomal incubations. Both in vitro and in vivo, the majority of the metabolites were 3alpha-OH,4,5alpha-dihydro derivatives. In monkeys, Org 30659 was mainly metabolized at the C3- and C17-positions in vivo. The 3-keto moiety was reduced to both 3beta-OH and 3alpha-OH substituents. In addition to phase I metabolites, glucuronic acid conjugates were observed in vivo. In monkey liver microsomes, the 6beta-OH metabolite of Org 30659 was the major metabolite present. Similar to the monkey liver microsomes, rabbit and human liver microsomes converted Org 30659 to the 6beta-OH metabolite. This metabolite was also the major metabolite in incubations with human hepatocytes.
Verhoeven
C H
CH
Department of Toxicology and Drug Disposition, University Centre for Pharmacy, Oss, The Netherlands.
Krebbers
S F
SF
Wagenaars
G N
GN
Booy
C J
CJ
Groothuis
G M
GM
Olinga
P
P
Vos
R M
RM
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008862:Microsomes, Liver / Q000378:metabolism; D009640:Norethindrone / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D014316:Tritium
D014316:Tritium; D009640:Norethindrone; C097629:Org 30659