Preliminary pharmacokinetics and metabolism of novel non-steroidal antiandrogens in the rat: relation of their systemic activity to the formation of a common metabolite.
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 1 h), but they form a common metabolite, the N-desalkyl derivative, RU 56279, 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.
Cousty-Berlin
D
D
Centre de Recherches Roussel Uclaf, Romainville, France.
Bergaud
B
B
Bruyant
M C
MC
Battmann
T
T
Branche
C
C
Philibert
D
D
D000726:Androgen Antagonists / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D009570:Nitriles / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012669:Seminal Vesicles / Q000187:drug effects
D000726:Androgen Antagonists; D007093:Imidazoles; D009570:Nitriles; C090226:4-(3,4,4-trimethyl-5-oxo-2-thioxo-1-imidazolidinyl)-2-(trifluoromethyl)benzonitrile; C086458:RU 58841