A possible explanation for the peripheral selectivity of a novel non-steroidal pure antiandrogen, Casodex (ICI 176,334).

The in vivo antiandrogenicity of Casodex has been confirmed and characterised. Androgen receptor (AR) binding assays of rat ventral prostate gland cytosols revealed a relative binding affinity (RBA) for the AR of 0.267 and a k1 of 1.25 x 10(-7) M for Casodex. In addition, the peripheral selectivity of Casodex relative to other non-steroidal antiandrogens was confirmed in that daily treatment of non-castrated rats with Casodex (25 mg kg-1) did not elicit any changes in serum LH and testosterone concentrations relative to vehicle-treated controls, whereas elevated serum LH and testosterone were observed in rats treated with flutamide (25 mg kg-1). The peripheral selectivity of Casodex in the intact male rat was related to the distribution of radiolabelled antiandrogen following intravenous injection. All tissues with the exception of the hypothalamus and cerebral cortex (CC) sequestered radioactivity such that the tissue:serum ratio (TSR) for the drug was greater than unity. In the testis, the TSR was less than unity 1 h after injection but approached unity 5 h after injection and was greater than unity 10 h after injection. This may be explained by the presence of a blood-testis barrier for the drug, resulting in delayed equilibration between the blood and testis tissue. By comparison, an order of magnitude lower amounts of radioactivity in the hypothalamus and CC were maintained for the 10 h period after injection. These data, together with known physicochemical properties of Casodex suggest that a blood-brain barrier exists for the drug which results in exclusion of this antiandrogen from central sites of androgen negative feedback and that this accounts for its peripherally selective antihormonal profile.