Excretion and metabolism of desogestrel in healthy postmenopausal women.
The metabolism of desogestrel (13-ethyl-11-methylene-18,19-dinor-17alpha-pregn-4-en-20-yn-17-ol), a progestagen used in oral contraceptives and hormone replacement therapy, was studied in vivo after a single oral administration of 150 microg [14C]-labeled desogestrel and 30 microg ethinylestradiol under steady state conditions to healthy postmenopausal women. After this oral administration, desogestrel was extensively metabolized. The dosed radioactivity was predominantly ( approximately 60%) excreted via urine, while about 35% was excreted via the feces. Desogestrel was metabolized mainly at the C3-, C5-, C6- and C13-CH(2)CH(3) positions. At the C3-position, the 3-keto moiety was found and in addition, 3beta-hydroxy and 3alpha-hydroxy groups were observed in combination with a reduced Delta(4)-double bond (5alpha-H). Hydroxy groups were introduced at the C6- (6beta-OH), the C13-ethyl (C13-CH(2)CH(2)OH) and possibly the C15- (15alpha-OH) position of desogestrel. Conjugation of the 3alpha-hydroxy moiety with sulfonic acid and conjugation with glucuronic acid were also major metabolic routes found for desogestrel in postmenopausal women. The 3-keto metabolite of desogestrel (the biologically active metabolite) was the major compound present in plasma at least up to 24 h after administration of the radioactive dose. Species comparison of the metabolic routes of desogestrel after oral administration indicates that in rats and dogs desogestrel is also mainly metabolized at the C3-position, similar to what is now found for postmenopausal women. Most other metabolic routes of desogestrel were found to differ between species. Finally, major metabolic routes found in the present study in postmenopausal women are in line with outcome of previous in vitro metabolism studies with human liver tissue (microsomes and postmitochondrial liver fractions) and intestinal mucosa.
Verhoeven
C H
CH
Department of Toxicology and Drug Disposition, Clinical Pharmacology Department, NV Organon, P.O. Box 20, 5340 BH, Oss, The Netherlands. carole.verhoeven@organon.com
Gloudemans
R H
RH
Peeters
P A
PA
van Lier
J J
JJ
Verheggen
F T
FT
Groothuis
G M
GM
Rietjens
I M
IM
Vos
R M
RM
D000284:Administration, Oral; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D017135:Desogestrel / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D004285:Dogs; D015914:Estrogen Replacement Therapy; D005243:Feces / Q000737:chemistry; D005260:Female; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008593:Menopause / Q000378:metabolism*; D015394:Molecular Structure; D045167:Progesterone Congeners / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D013045:Species Specificity
D020719:Glucuronides; D045167:Progesterone Congeners; D017135:Desogestrel