TZP-4238, a new steroidal antiandrogen, is an orally active drug in rats and dogs. The effects of TZP-4238 on the androgen receptor and androgen content were examined in comparison with other antiandrogens in rats
The prostate DHT levels decreased markedly within 4-8 hr after a single oral administration of TZP-4238 8mg/kg. The prostatic testosterone concentrations fell below the detection limit (5pg/g of tissue) at 4-12 hr after the initiation of treatment. The plasma testosterone level also fell to 60% of the control level after 4-8 hr and then returned to the normal range. Eighty percent of DHT present in normal prostatic tissue was located in the nuclear fraction. TZP-4238 reduced the concentration of DHT in nuclei to 50% of the normal level. The concentration of the plasma drug which induced a 50% decrease in the prostatic DHT, the IC₅₀, was about 10ng/ml, while the IC₅₀ value for plasma testosterone was 30-50ng/ml. After oral administration of 15-OH TZP-4238, the main metabolite, the level of plasma testosterone was significantly elevated above the control level. The androgen receptor level was markedly reduced at 24 hr following castration and returned to the normal range within 5 hr of a single injection of testosterone. TZP-4238 reduced the nuclear androgen receptor level to 60% at 24 hr after a single oral dose and then, the receptor content returned to its original level. Both 15-OH TZP-4238 and cyproterone acetate also reduced the androgen receptor and DHT contents to 50%. A series of in vivo studies demonstrated that TZP-4238 inhibited the uptake of testosterone and the decrease of DHT and testosterone, and decreased the nuclear androgen receptor in the rat prostate.