HEPATIC-METABOLISM AND DISTRIBUTION OF MIFEPRISTONE AND ITS METABOLITES IN RATS
HEPATIC-METABOLISM AND DISTRIBUTION OF MIFEPRISTONE AND ITS METABOLITES IN RATS
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DOI：
10.1093/humrep/9.suppl_1.40
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发表时间：
1994-06-01
影响因子：
6.1
通讯作者：
LAHTEENMAKI, P
中科院分区：
文献类型：
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作者：
HEIKINHEIMO, O;PESONEN, U;LAHTEENMAKI, P
研究了雌性Wistar大鼠口服米非司酮10 mg/kg后肝脏代谢的变化。用大鼠肝脏提取米非司酮是有效的，去除80%的米非司酮。在吸收期，门静脉血药浓度比全身血药浓度高10倍以上。全身血清中米非司酮单去甲基化、二去甲基化和羟化代谢物浓度较低，表明该代谢物也被大鼠肝脏有效排泄。研究了反复口服10 mg/kg米非司酮和肥胖Zucker大鼠血清、脑、肌肉和脂肪组织中米非司酮及其去甲基化代谢物的分布。米非司酮的个体血清浓度变化很大，从24-482 ng/ml；瘦肉大鼠和肥胖大鼠血清SE平均浓度（+/- 86）分别为167（+/- 86）和211 (+/- 62)ng/ml。每只动物脑内均可检测到米非司酮，其浓度为血清浓度的28%。肌肉组织和血清中米非司酮的浓度大致相似。脂肪组织能有效地浓缩米非司酮，其在脂肪中的浓度比在血清中的浓度高40倍。瘦型和肥胖型动物的米非司酮浓度仅在脑组织中有统计学差异（P < 0.05）。血清米非司酮浓度与脑、肌、脂肪组织浓度呈显著相关（P < 0.05）。去甲基化代谢物的分布与米非司酮大致相似。然而，在肥胖动物中，它们的浓度在各组织类型中均显著升高（P < 0.02）。血清代谢物浓度与组织代谢物浓度呈显著相关（P < 0.001）。米非司酮在大鼠和人之间的药代动力学差异很大，最可能的解释是大鼠血清中缺乏米非司酮的高亲和力结合蛋白。脑组织中米非司酮的低浓度表明米非司酮进入中枢神经组织的程度有限。这也可以解释米非司酮在人体内某些中枢介导效应的剂量依赖性。
The hepatic metabolism of mifepristone was studied in female Wistar rats following oral administration of 10 mg/kg. The extraction of mifepristone by the rat liver was effective, eliminating 80% of the mifepristone. During the absorption phase, the portal serum concentrations of mifepristone were over 10-fold higher than those measured in systemic serum. The serum concentrations of the monodemethylated, didemethylated and hydroxylated metabolites of mifepristone were lower in systemic serum, indicating that the metabolites were also effectively excreted by the rat liver. The distribution of mifepristone and its demethylated metabolites between serum, brain, muscle and adipose tissue was studied in lean and obese Zucker rats following repeated oral administration of 10 mg/kg. The individual serum concentrations of mifepristone varied considerably, from 24-482 ng/ml; the mean (+/- SE) serum concentrations for lean and obese rats were 167 (+/- 86) and 211 (+/- 62) ng/ml respectively. Mifepristone could be measured in brain in each animal, its concentrations being 28% of those measured in serum. Muscle tissue and serum contained approximately similar concentrations of mifepristone. Adipose tissue effectively concentrated mifepristone, and its concentrations were 40-fold higher in fat than in serum. The difference in the concentrations of mifepristone between the lean and obese animals was statistically significant only in brain tissue (P < 0.05). The serum concentrations and brain, muscle and adipose tissue concentrations of mifepristone were significantly correlated (P < 0.05). The distribution of the demethylated metabolites was roughly similar to that of mifepristone. However, their concentrations were significantly higher (P < 0.02) in the obese animals in each tissue type investigated. Also, the serum and tissue concentrations of the metabolites were significantly correlated (P < 0.001). The pharmacokinetics of mifepristone differ profoundly between rat and man, the most likely explanation being lack of high-affinity binding protein for mifepristone in rat serum. The low concentrations of mifepristone in the brain tissue suggest limited entry of mifepristone into central nervous tissue. This might also explain the dose-dependent nature of some centrally mediated effects of mifepristone in man.