On the Mechanism of the Anti-androgenic Action ofFlutamide (α-α-α-Trifluoro-2-methyl-4'-nitro-m-propionotoluidide)in the Rat

The effect of [α-α-α-trifluoro-2- methyl-4'-nitro-m-propionotoluidide], flutamide, on 3H-testosterone and 3H-dihydrotestosterone uptake and metabolism in rat ventral prostate and semial vesicle has been studied and compared to cyproterone acetate. Testosterone-treated castrated rats were given an oral dose of 15 mg/kg of either drug for 3–7 days; neither agent suppressed 3H-testosterone uptake by the tissue at 60 min following an intraperitoneal injection of the labeled steroid given 24 hr after the last dose of drug. Both, however, fully antagonized the effect of testosterone on maintaining prostate and seminal vesicle weights in these rats. In contrast to these results both flutamide and cyproterone acetate, administered p. o. at IS mg/kg/4 days, markedly inhibited 3H-testosterone uptake and retention by prostate and prostate nuclei when labeled androgen was given 3 hr following the last dose of the drug. Similarly, a single dose of these drugs co-administered via ip injection with either 3H-testosterone or 3H-dihydrotestosterone inhibited uptake and retention of the labeled androgen by prostate whole tissue and nuclei. Flutamide was demonstrated to inhibit the formation of the nuclear 3H protein-3H androgen complex in addition to depressing whole tissue uptake and retention of 3H-testosterone. Similar effects were noted with cyproterone acetate. The effects of flutamide on prostate tissue in vitro were also studied and were shown to be similar, though not as marked, to those observed in vivo; again the effects of flutamide were similar to those of cyproterone acetate. The in vitro results suggest that flutamide might achieve its results, at least in part, through an active metabolite. Similar to cyproterone acetate, flutamide had no marked effect on the metabolic conversion by the rat ventral prostate of 3H-testosterone to its active metabolite 3H-dihydrotestosterone or to any of the other metabolic products. These results are consistent with the conclusion that flutamide, or a metabolite, exerts its antiandrogenic effects on male secondary sex structures by an inhibition of androgen uptake and/or inhibition of nuclear binding of the androgens in the target tissues. (Endocrinology94: 532, 1974)