モルモットにおけるChlormadinone Acetateの生体内変換と去勢ラットにおけるTestosterone-3HとChlormadinoneAcetate-3Hの前立腺への取り込みについて

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The metabolic fate and distribution of the anti-androgenic agent, 17α-acetoxy-6-chloropregna-4, 6-diene-3, 20-dione (chlormadinone acetate, CMA), was investigated using guinea-pigs and rats. In order to elucidate the metabolic outcome, chlormadinone acetate was labelled with 3H at position C-1 and with deuterium at methyl moiety of the 17α-acetate. Guinea-pigs were maintained for 7 days on a diet containing 1% chlormadinone acetate having a ratio of d2 /d0=1 and then for 1 day on a diet containing 1% chlormadinone acetate having radioactivity. The isolation and purification of the urinary and fecal metabolites were usually carried out in the manner shown in Fig. 1 and 2. The metabolites identified were as follows : the parent drug, monohydroxychlormadinone acetate having the additional hydroxy function in the steroid skeleton, 15β-hydroxy, 2α-, 2β-hydroxy and unknown position, dihydroxy chlormadinone acetate, 2α-, 3β-dihydroxy, 2α-, 3α-dihydroxychlormadinone acetate. Further, three dechlorinated and reduced metabolites were also isolated from urine and feces. These were 17α-acetoxy-5α-pregnane-3β-ol-20-one and its isomer, and 17α-acetoxy-5β-pregnane-2β, 3β, 15α-triol-20-one. But 3β-hydroxychlormadinone acetate possessed with anti-androgenic activity, one of the main metabolites in humans and rats, was not found in the excreta of the guinea-pigs. However, the main metabolite on the prostate of the guinea-pigs and rats and 3β-hydroxychlormadinone acetate. Chlormadinone acetate causes regression of the seminal vesicle and prostate in oral administration to a mammalian. It was therefore hypothesized that chlormadinone acetate might inhibit the uptake and retention of testosterone in these tissues. To elucidate this hypothesis, the accumulation of testosterone-3 H and chlormadinone acetate-3 H in several organs was determined on castrated rats and normal rats, respectively. When 1.0μM of testosterone-3H was given to the castrated rats, a maximal accumulation of radioactivity resulted in seminal vesicle and prostate at 15-120 min. While the treatment of chlormadinone acetate significantly prevented the accumulation of testosterone-3 H in the seminal vesicle and prostate, but levels in fat and muscle were not evident. In addition, to prove the accumulation of chlormadinone acetate in androgen target tissues, 3 μM of chlormadinone acetate-3 H was similarly administered to castrated rats. The uptake of chlormadinone acetate on the target organs was higher than that in normal rats at 5-30 min.
日本内分泌学会の論文

モルモットにおけるChlormadinone Acetateの生体内変換と去勢ラットにおけるTestosterone-<SUP>3</SUP>HとChlormadinoneAcetate-<SUP>3</SUP>Hの前立腺への取り込みについて

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