Relative potencies of Flutamide and Casodex: Preclinical studies

After 3 h of incubation at room temperature, hydroxyFlutamide, the active metabolite of Flutamide (Eulexin), and Casodex (bicalutamide), an analog of Flutamide, have comparable potency to displace [H-3]R1881 from the human prostate and rat ventral prostate androgen receptors contrary to the previous claims that Casodex was four times more potent using different incubation conditions. Binding data, in fact, must be interpreted with caution, since they are very much dependent upon the duration and temperature of incubation. In the more appropriate intact cell situation, hydroxyFlutamide is approximately three times more potent than Casodex at inhibiting dihydrotestosterone-stimulated proliferation of androgen-sensitive mouse Shionogi carcinoma cells in vitro. Under in vivo conditions, in the orchiectomized rat supplemented with androstenedione implants, Flutamide is about three times more potent than Casodex al inhibiting ventral prostate and seminal vesicle weight. When both compounds were administered for 7 days to intact rats, Flutamide and Casodex showed similar apparent potency. However, taking into account the much higher plasma levels of testosterone and dihydrotestosterone in intact animals treated with Flutamide compared with those treated with Casodex, the estimated potency of Flutamide in the intact rat is also at least three times higher than that of Casodex. The present data, contrary to previous claims based upon the inappropriate intact rat model clearly show that Flutamide is at least three times more potent than Casodex in rat and mouse tissues. These data are opposite to those obtained in the inappropriate intact rat model where Casodex was reported to be five to ten times more potent than Flutamide. Using more appropriate models of androgen action, the present data thus indicate a 15- to 30-fold lower estimate of the potency of Casodex. Since the choice of the dose of Casodex to be used for the treatment of prostate cancer patients is based upon such a large overestimate of the true potency of Casodex, the present data should help the choice of a more appropriate dose of this antiandrogen for the treatment of prostate cancer.