TZP-4238 suppresses plasma testosterone in humans, but its action on the androgen biosynthesis pathway has not been established. Therefore, we researched the testicular testosterone level and the testosterone biosynthesis pathway in vitro in rats before and after receiving a single or continuous oral dose of TZP-4238. The total testosterone fell to 60% of the basal level within 3-8 hr (p < 0.05) and then returned to the control concentration by 24 hr after a single administration of 32 mg/kg. The alteration of the plasma testosterone level correlated well with that of the intratesticular level, which was decreased to 50% at 3-8 hr and recovered to the control level by 24 hr. However, the decrement of the plasma LH level at 3-8 hr after a single oral administration was slight and it then returned to the original level at 12 hr. During the 8 weeks of daily administration of 0.5 mg/kg of TZP-4238 or chlormadiNone acetate to dogs, the plasma testosterone levels were slightly lower than the basal extent. In vitro experiments were conducted on the rat testis using the exogenous precursor steroids 20 alpha-hydroxycholesterol, pregnenolone and progesterone, in various steps leading to the biosynthesis of testosterone. Trilostane acted at 3 beta-hydroxysteroid dehydrogenase (50% inhibition concentration, IC50 was 1 microM), ketoconazole inhibited the 17 alpha-hydroxylase, and C20, 22- and C17, 20-lyase activities, with an IC50 of 1-50 microM. Cyproterone acetate inhibited both the 3 beta-hydroxysteroid dehydrogenase (IC50;50 microM) and C17, 20-lyase. On the other hand, TZP-4238 exhibited a weaker inhibition of 3 beta-hydroxysteroid dehydrogenase (IC50; 100 microM) than cyproterone acetate, but not of hydroxylase and lyase. Though TZP-4238 did not inhibit the increased testosterone level induced by hCG, trilostane markedly inhibited the effect induced by hCG.(ABSTRACT TRUNCATED AT 250 WORDS)
Honma S; Takezawa Y; Yamanaka H
Pharmacokinetics Research Department, Teikoku Hormone Mfg. Co. LTD, Kawasaki, Japan.
Nippon Naibunpi Gakkai Zasshi, 71: 5, 1995 Jul 20, 679-94