PRELIMINARY PHARMACOKINETICS AND METABOLISM OF NOVEL NONSTEROIDAL 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 thioh ydantoins. Their pharmacokinetics and principal metabolic profiles hav e been evaluated in rat plasma after intravenous administration of a 1 0 mg/kg dose. Both compounds disappear relatively rapidly from the pla sma (elimination half-life of the order of 1 h), but they form a commo n metabolite, the N-desalkyl derivative, RU 56279, which is eliminated much more slowly. The percentage transformations of each into RU 5627 9, estimated from the AUCs of the metabolite compared with the AUC obt ained after administration of RU 56279 itself, were respectively 1% an d 77%. In parallel, their in vivo activity, as well as that of their m etabolites, was determined with respect to parameters related to syste mic 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 per centage formation of this metabolite and the systemic antiandrogenic a ctivity of the compounds. Thus, the pharmacological profile of RU 5884 1 which displays a potent local antiandrogenic activity without system ic effects can be related to its very low propensity to form the N-des alkyl metabolite.