Title
Preliminary pharmacokinetics and metabolism of novel non-steroidal
antiandrogens in the rat: relation of their systemic activity to the
formation of a common metabolite.
Author
Cousty-Berlin D, Bergaud B, Bruyant MC, Battmann T, Branche C, Philibert D
Address
Centre de Recherches Roussel Uclaf, Romainville, France.
Source
J Steroid Biochem Mol Biol, 51: 1-2, 1994 Oct, 47-55
Abstract
The non-steroidal antiandrogens, RU 58841 and RU 56187 are amongst the most active of a
new series of N-substituted aryl hydantoins or thiohydantoins. Their pharmacokinetics and
principal metabolic profiles have been evaluated in rat plasma after intravenous
administration of a 10 mg/kg dose. Both compounds disappear relatively rapidly from the
plasma (elimination half-life of the order of 1h), but they form a common metabolite, the
N-desalkyl derivative, RU56279, which is eliminated much more slowly. The percentage
transformations of each into RU 56279, estimated from the AUCs of the metabolite compared
with the AUC obtained after administration of
RU 56279 itself, were respectively 1% and 77%. In parallel, their in vivo activity, as
well as that of their metabolites, was determined with respect to parameters related to
systemic antiandrogenic effects (prostate and seminal vesicle weights). The results showed
that: (1) the common metabolite, RU 56279, is clearly antiandrogenic; (2) there appears to
be a relationship between the percentage formation of this
metabolite and the systemic antiandrogenic activity of the compounds.
Thus, the pharmacological profile of RU 58841 which displays a potent local antiandrogenic
activity without systemic effects can be related to its very low propensity to form the
N-desalkyl metabolite.
Language of Publication
English
Unique Identifier
95034339