STUDIES ON THE HYDROGENATION OF THE PROGESTAGEN DIENOGEST IN-VIVO ANDIN-VITRO IN THE FEMALE RABBIT

The biotransformation of the progestagen dienogest (17 alpha-cyanometh yl-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 rat s. In vivo, in the female rabbit, H-3-dienogest was the subject of an Extensive biotransformation. A significant difference between the comp osition of the urinary and biliary metabolite patterns of dienogest wa s found. While in the urinary metabolite pattern more polar metabolite s dominated, in bile of animals with a bile fistula, a dienogest metab olite of medium polarity was prevalent. This main metabolite of dienog est was identified by MS, H-1- and C-13-NMR spectroscopy and CD measur ement of ail enzymatic dehydrogenation product as the tetrahydro metab olite 17 alpha-cyanomethyl-5 alpha-estr-9-en-3 beta, 17 beta-diol. Thu s, in vivo, the 4,9-dien-3-oxo-19-norsteroid dienogest is hydrogenated to a 5 alpha H-9-en metabolite. In vitro, however, H-3-dienogest was only poorly transformed by liver homogenates from both species, wherea s H-3-levonorgestrel and H-3-3-keto-desogestrel were converted partial ly by liver homogenates from female rabbits and completely by liver ho mogenates from female rats. The principal biotransformation reactions of levonorgestrel and 3-ketodesogestrel were the reduction of the 3-ox o group to 3-OH and the 5 beta- and 5 alpha-hydrogenation of the 4-dou ble bond by homogenates of female rabbit liver and female rat liver, r espectively. A dihydro metabolite of dienogest, in which the 3-oxo gro up had been reduced to 3-OH, was isolated in small amounts from the in cubation with rabbit liver homogenate. The data indicate that the enzy matic 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 ill the steroid molecule. (C) 1998 by Elsevier Science Inc.