The pharmacokinetics of mifepristone in humans reveal insights into differential mechanisms of antiprogestin action
The pharmacokinetics of mifepristone in humans reveal insights into differential mechanisms of antiprogestin action
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DOI：
10.1016/s0010-7824(03)00077-5
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发表时间：
2003-12-01
期刊：
影响因子：
2.9
通讯作者：
Lähteenmäki, P
中科院分区：
文献类型：
--
作者：
Heikinheimo, O;Kekkonen, R;Lähteenmäki, P
米非司酮的药代动力学的特征在于快速吸收，25-30小时的长半衰期，以及在摄入大于或等于100 mg剂量的药物后的高微摩尔血清浓度。血清转运蛋白-α 1-酸性糖蛋白（AAG）-调节米非司酮在人体内的血清动力学。与AAG的结合限制了米非司酮的组织利用度，解释了其低分布容积和低代谢清除率（0.55 L/kg/d）。此外，单次摄入剂量超过100 mg的米非司酮后，血清中米非司酮水平相似，这可以用血清AAG结合能力饱和来解释。米非司酮通过去甲基化和羟基化广泛代谢，最初的代谢步骤由细胞色素P-450酶CYP 3A 4催化。三个最接近的代谢产物，即米非司酮的单去甲基化、去二甲基化和羟基化代谢产物，都对人孕酮和糖皮质激素受体保持相当大的亲和力。此外，这三种代谢物的血清水平范围与母体米非司酮相似。因此，米非司酮及其代谢产物的组合库似乎是米非司酮的生物学作用的原因。最近关于终止妊娠和紧急避孕的临床研究集中在米非司酮剂量的优化上。在这些研究中，很明显，终止妊娠的有效剂量与紧急避孕所需的剂量不同-米非司酮在10 mg剂量下对紧急避孕有效，这导致线性药代动力学。然而，大于或等于200 mg剂量的米非司酮，需要最佳的米非司酮流产效果，导致血清AAG饱和，因此非线性药代动力学。根据药代动力学数据，可以推测米非司酮用于终止妊娠和紧急避孕的剂量可以分别减少到约100 mg和2-5 mg。新合成的、更有选择性的抗孕激素是否在临床竞技场上更有效还有待观察。(C)2003年爱思唯尔科学公司All rights reserved.
The pharmacokinetics of mifepristone is characterized by rapid absorption, a long half-life of 25-30 h, and high micromolar serum concentrations following ingestion of doses of greater than or equal to 100 mg of the drug. The serum transport protein-alpha 1-acid glycoprotein (AAG)-regulates the serum kinetics of mifepristone in man. Binding to AAG limits the tissue availability of mifepristone, explaining its low volume of distribution and low metabolic clearance rate of 0.55 L/kg per day. In addition, the similar serum levels of mifepristone following ingestion of single doses exceeding 100 mg can be explained by saturation of the binding capacity of serum AAG. Mifepristone is extensively metabolized by demethylation and hydroxylation, the initial metabolic steps being catalyzed by the cytochrome P-450 enzyme CYP3A4. The three most proximal metabolites, namely, monodemethylated, didemethylated and hydroxylated metabolites of mifepristone, all retain considerable affinity toward human progesterone and glucocorticoid receptors. Also, the serum levels of these three metabolites are in ranges similar to those of the parent mifepristone. Thus, the combined pool of mifepristone-plus its metabolites-seems to be responsible for the biological actions of mifepristone. Recent clinical studies on pregnancy termination and emergency contraception have focused on optimization of the dose of mifepristone. In these studies it has become apparent that the doses efficient for pregnancy termination differ from those needed in emergency contraception-mifepristone is effective in emergency contraception at a dose of 10 mg, which results in linear pharmacokinetics. However, the greater than or equal to200 mg doses of mifepristone, needed for optimal abortifacient effects of mifepristone result in saturation of serum AAG and thus nonlinear pharmacokinetics. In view of the pharmacokinetic data, it may be speculated that dosing of mifepristone for pregnancy termination and for emergency contraception could be reduced to approximately 100 mg and 2-5 mg, respectively. It remains to be seen whether the newly synthesized, more selective antiprogestins will prove more efficacious in the clinical arena. (C) 2003 Elsevier Science Inc. All rights reserved.