Studies on the hydrogenation of the progestagen dienogest in vivo and in vitro in the female rabbit.
The biotransformation of the progestagen dienogest (17 alpha-cyanomethyl-17 beta-hydroxy-4,9-estradien-3-one) was studied in vivo in female rabbits and in vitro by liver homogenates from female rabbits and rats. In vivo, in the female rabbit, 3H-dienogest was the subject of an extensive biotransformation. A significant difference between the composition of the urinary and biliary metabolite patterns of dienogest was found. While in the urinary metabolite pattern more polar metabolites dominated, in bile of animals with a bile fistula, a dienogest metabolite of medium polarity was prevalent. This main metabolite of dienogest was identified by MS, 1H- and 13C-NMR spectroscopy and CD measurement of an enzymatic dehydrogenation product as the tetrahydro metabolite 17 alpha-cyanomethyl-5 alpha-estr-9-en-3 beta,17 beta-diol. Thus, in vivo, the 4,9-dien-3-oxo-19-norsteroid dienogest is hydrogenated to a 5 alpha H-9-en metabolite. In vitro, however, 3H-dienogest was only poorly transformed by liver homogenates from both species, whereas 3H-levonorgestrel and 3H-3-keto-desogestrel were converted partially by liver homogenates from female rabbits and completely by liver homogenates from female rats. The principal biotransformation reactions of levonorgestrel and 3-ketodesogestrel were the reduction of the 3-oxo group to 3-OH and the 5 beta- and 5 alpha-hydrogenation of the 4-double bond by homogenates of female rabbit liver and female rat liver, respectively. A dihydro metabolite of dienogest, in which the 3-oxo group had been reduced to 3-OH, was isolated in small amounts from the incubation with rabbit liver homogenate. The data indicate that the enzymatic hydrogenation of the 4-double bond of the 4,9-dien-3-oxo steroid dienogest is inhibited in vitro. The hindered hydrogenation reaction in vitro has to be seen in association with the 9-double bond in the steroid molecule.
Hobe
G
G
Hans-Knöll Institute for Natural Products Research, Jena, Germany.
Schön
R
R
Hajek
M
M
Undisz
K
K
Härtl
A
A
D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D003276:Contraceptives, Oral / Q000378:metabolism; D017135:Desogestrel / Q000378:metabolism; D005260:Female; D006865:Hydrogenation; D016912:Levonorgestrel / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000652:urine; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar
D003276:Contraceptives, Oral; C044815:etonogestrel; C023635:dienogest; D016912:Levonorgestrel; D009277:Nandrolone; D017135:Desogestrel