Tanaka S, Honma S, Kambegawa A
Nihon Naibunpi Gakkai Zasshi. 1980 Aug 20;56(8):1116-29. doi: 10.1507/endocrine1927.56.8_1116.
The metabolic fate and distribution of the anti-androgenic agent, 17 alpha-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 17alpha-acetate. Guineapigs 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, 15 beta-hydroxy, 2 alpha-, 2 beta-hydroxy and unknown position, dihydroxy chlormadinone acetate, 2 alpha-, 3 beta-dihydroxy, 2 alpha-, 3 alpha-dihydroxychlormadinone acetate. Further, three dechlornated and reduced metabolites were also isolated from urine and feces. These were 17 a-acetoxy-5a-pregnane-3 beta-ol-20-one and its isomer, and 17-acetoxy-5 beta-pregnane-2 beta, 3 beta, 15a-triol-20-one. But 3 beta-hydroxychlormadinone acetate possessd 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 3 beta-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-3H and chlormadinone acetate-3H in several organs was determined on castrated rats and normal rats, respectively. When 1.0 muM of testosterone-3H was given to the castrated rats, a maximal accumulation of radioactivity resulted in seminal vesicle and prostate at 15 approximately 120 min. While the treatment of chlormadinone acetate significantly prevented the accumulation of testosterone-3H 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 muM of chlormadinone acetate-3H was similarly administered to castrated rats. The uptake of chlormadinone acetate on the target organs was higher than that in normal rats at 5 approximately 30 min.
使用豚鼠和大鼠研究了抗雄激素药物17α-乙酰氧基-6-氯孕甾-4,6-二烯-3,20-二酮（醋酸氯地孕酮，CMA）的代谢命运和分布。为了阐明代谢结果，醋酸氯地孕酮在C-1位用3H标记，在17α-醋酸酯的甲基部分用氘标记。豚鼠在含1%醋酸氯地孕酮（d2/d0 = 1）的饮食中维持7天，然后在含1%有放射性的醋酸氯地孕酮的饮食中维持1天。尿液和粪便代谢物的分离和纯化通常按照图1和图2所示的方式进行。鉴定出的代谢物如下：母体药物、在甾体骨架中具有额外羟基功能的单羟基醋酸氯地孕酮、15β-羟基、2α-、2β-羟基及位置未知的、二羟基醋酸氯地孕酮、2α-、3β-二羟基、2α-、3α-二羟基醋酸氯地孕酮。此外，还从尿液和粪便中分离出了三种脱氯和还原的代谢物。它们是17α-乙酰氧基-5α-孕烷-3β-醇-20-酮及其异构体，以及17-乙酰氧基-5β-孕烷-2β,3β,15α-三醇-20-酮。但是在豚鼠的排泄物中未发现具有抗雄激素活性的3β-羟基醋酸氯地孕酮，它是人和大鼠的主要代谢物之一。然而，豚鼠和大鼠前列腺中的主要代谢物是3β-羟基醋酸氯地孕酮。醋酸氯地孕酮口服给药给哺乳动物会导致精囊和前列腺萎缩。因此推测醋酸氯地孕酮可能会抑制这些组织中睾酮的摄取和保留。为了阐明这一假设，分别测定了去势大鼠和正常大鼠几种器官中睾酮-3H和醋酸氯地孕酮-3H的积累情况。当给去势大鼠注射1.0μM的睾酮-3H时，在15至120分钟时精囊和前列腺中放射性积累达到最大值。而醋酸氯地孕酮处理显著阻止了睾酮-3H在精囊和前列腺中的积累，但在脂肪和肌肉中的水平没有明显变化。此外，为了证明醋酸氯地孕酮在雄激素靶组织中的积累，同样给去势大鼠注射3μM的醋酸氯地孕酮-3H。在5至30分钟时，醋酸氯地孕酮在靶器官上的摄取高于正常大鼠。
