[The effect of antiandrogen TZP-4238 on corticosteroid hormone in the dog].

Abstract

We studied the adrenosuppressive effect of antiandrogen TZP-4238 and its metabolites. The binding affinity for the corticosteroid receptor using rat hepatic cytosol was in the order 11-OH TZP-4238 > 11, 15-(OH)2 TZP-4238 >> TZP-4238 > or = 15-OH TZP-4238 > 11-keto TZP-4238. Male beagle dogs aged 1-6 years were randomly divided into TZP-4238 (0.05, 0.5mg/kg) treatment groups and CMA (0.5mg/kg) treatment group. Each group was administered the drug per os every day for 8 weeks. Plasma cortisol, TZP-4238 and its metabolite levels were measured by on-line coupling of liquid chromatography with thermospray or atmospheric pressure ionization mass spectrometry using selective ion monitoring (LC-MS/SIM). LC-MS/SIM provided a sensitive and reliable method of unequivocal confirmation of the presence of steroidal drugs in the plasma. The plasma cortisol level was lowered below 1 ng/ml at 1 week after oral administration of TZP-4238 at 0.5mg/kg or CMA at 0.5mg/kg. The decline continued throughout the treatment for 8 weeks. Upon termination of administration, the cortisol level returned to the normal level (6ng/ml) by 4 weeks. However in the group given 0.05mg/kg TZP-4238, the cortisol level remained within the normal range. To analyze the cortisol decreasing mechanism, we administered TZP-4238 at 0.5mg/kg for 7 days to one beagle dog. When the plasma 11-OH TZP-4238 level was increased, the cortisol level decreased time dependently and the concentration of plasma 11-OH TZP-4238 which induced 50% inhibition was 2ng/ml. The decrease in the plasma cortisol level was highly correlated to the extent of the increase of the plasma 11-OH TZP-4238 (r2 = 0.840). We conclude that the adrenosuppressive effect of antiandrogen TZP-4238 is not due to TZP-4238 itself but its metabolite 11-OH TZP-4238.