Nonsteroid antiandrogen inhibiting effect on testosterone metabolism in rat prostate and liver.

Abstract

The effect of nonsteroid antiandrogen flutamide on 3H-testosterone (3H-T) metabolism in vitro was studied in Wistar male rat prostatic and hepatic homogenates. Flutamide was administered per os in a dose of 25 mg/kg daily for 3, 10 or 30 consecutive days. Following 30 days 5 alpha-dihydrotestosterone (DHT) formation in the prostate was reduced by 50%. In castrated animals antiandrogen abolished the recovering action of testosterone propionate (TP) on 5 alpha-reductase activity. When added to incubation medium flutamide proved ineffective, while hydroxyflutamide appeared to decrease DHT formation. The metabolic utilization of 3H-T in the liver of rats receiving flutamide for 30 days was found to be 3 times lower. The formation of DHT, androsterone, ethiocholanolone and androstenedione was substantially suppressed. In castrated rats, both treated and nontreated with TP, flutamide also inhibited the formation of steroid metabolites of 3H-T. Synergism to flutamide and TP action on androgen metabolism in the liver is suggested to be related to antiandrogen ability of interaction with an unusual estrogen-binding protein of rat liver. The decrease in DHT formation induced by flutamide may play a role in the mechanism of its therapeutic action in prostatic cancer patients.