Heikinheimo O, Kontula K, Croxatto H, Spitz I, Luukkainen T, Lähteenmäki P
J Steroid Biochem. 1987 Feb;26(2):279-84. doi: 10.1016/0022-4731(87)90083-5.
Using Chromosorb chromatography and HPLC, we measured the plasma concentrations of RU 486, and its monodemethylated (RU 42633), didemethylated (RU 42848) and alcoholic nondemethylated (RU 42698) metabolites up to 72 h following oral ingestion of 100 mg of RU 486 by five female volunteers. The peak plasma level of RU 486 (4.5 mumol/l) occurred within 1 h after ingestion of the compound; at this point significant amounts of the metabolites were also present in the plasma. After the initial redistribution within 6 h the plasma concentrations of RU 486 and three of its metabolites measured remained stable for 24 h. Concentrations of the monodomethylated metabolite exceeded those of the parent steroid during the time period measured, whereas the concentrations of the didemethylated and alcoholic metabolites were lower than those of RU 486, but still notable. At 72 h the concentrations of all the four steroids were still in the micromolar range. The relative binding affinities of these metabolites to human endometrial and myometrial progesterone receptors as well as to human placental glucocorticoid receptors were determined in vitro. The affinity of RU 486 for the human uterine progesterone receptor (Kd = 1.3 X 10(-9) M for RU 486) was higher than that of progesterone but lower than that of ORG-2058, a potent synthetic progestin. The relative binding affinities of the monodemethylated, alcoholic and didemethylated metabolites to the progesterone receptor were 21, 15 and 9%, respectively, compared with the parent compound RU 486; each was lower than that of progesterone (43%). RU 486 had an approx. 4-fold higher relative binding affinity to the glucocorticoid receptor than dexamethasone. Interestingly, the relative binding affinities of the metabolites studied to the human glucocorticoid receptor exceeded those of dexamethasone or cortisol. Compared with the parent compound RU 486, they were 61, 48 and 45% for the monodemethylated, alcoholic and didemethylated metabolites, respectively; each was higher than that of dexamethasone (23%). The affinity of dexamethasone to the human glucocorticoid receptor was 1.6 X 10(-9) M. These data indicate that the pool of certain metabolites of RU 486 may contribute to a significant extent to the antiprogestagenic (23-33%) and even greater extent to the antiglucocorticoid (47-61%) effects of RU 486.
我们采用Chromosorb色谱法和高效液相色谱法（HPLC），对5名女性志愿者口服100毫克米非司酮后72小时内米非司酮及其单去甲基化（RU 42633）、双去甲基化（RU 42848）和醇性未去甲基化（RU 42698）代谢物的血浆浓度进行了测定。米非司酮的血浆峰值水平（4.5微摩尔/升）在摄入该化合物后1小时内出现；此时血浆中也存在大量代谢物。在最初6小时内重新分布后，所测定的米非司酮及其三种代谢物的血浆浓度在24小时内保持稳定。在所测定的时间段内，单去甲基化代谢物的浓度超过了母体类固醇的浓度，而双去甲基化和醇性代谢物的浓度低于米非司酮，但仍较为显著。在72小时时，所有四种类固醇的浓度仍处于微摩尔范围内。在体外测定了这些代谢物与人子宫内膜和子宫肌层孕酮受体以及人胎盘糖皮质激素受体的相对结合亲和力。米非司酮与人子宫孕酮受体的亲和力（米非司酮的解离常数Kd = 1.3×10⁻⁹ M）高于孕酮，但低于强效合成孕激素ORG - 2058。与母体化合物米非司酮相比，单去甲基化、醇性和双去甲基化代谢物与孕酮受体的相对结合亲和力分别为21%、15%和9%；每种均低于孕酮（43%）。米非司酮与糖皮质激素受体的相对结合亲和力比地塞米松高约4倍。有趣的是，所研究的代谢物与人糖皮质激素受体的相对结合亲和力超过了地塞米松或皮质醇。与母体化合物米非司酮相比，单去甲基化、醇性和双去甲基化代谢物的相对结合亲和力分别为61%、48%和45%；每种均高于地塞米松（23%）。地塞米松与人糖皮质激素受体的亲和力为1.6×10⁻⁹ M。这些数据表明，米非司酮的某些代谢物库可能在很大程度上促成了米非司酮的抗孕激素作用（23 - 33%），甚至在更大程度上促成了其抗糖皮质激素作用（47 - 61%）。
