米非司酮3种晶型的制备及其在大鼠体内药动学研究  

Preparation of three crystals of mifepristone and its pharmacokinetics in rats

作　　者：梁宇 邢逞[2] 周启蒙[1] 孔德文 赵晓悦 宋俊科[1] 吕扬[2] 杜冠华[1] LIANG Yu;XING Cheng;ZHOU Qi-meng;KONG De-wen;ZHAO Xiao-yue;SONG Jun-ke;Lü Yang;DU Guan-hua(Bejing Key Laboratory of Drug Target and Screening Research,Chinese Academy of Medical Sciences and Peking Union Medical College;Research Centre of Polymorphic Drugs,Bejing Key Laboratory of Polymorphic Drugs,Instirute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院北京协和医学院药物所,药物筛选研究中心,药物靶点研究和新药筛选北京市重点实验室 [2]中国医学科学院北京协和医学院药物所,药物晶型研究中心,晶型药物研究北京市重点实验室,北京100050

出　　处：《中国新药杂志》2020年第19期2251-2259,共9页Chinese Journal of New Drugs

基　　金：国家重点研发计划专项(2016YFC1000905);中国医学科学院医学与健康科技创新工程项目(2017-I2M-1-010)。

摘　　要：目的:通过不同方法制备米非司酮(mifepristone)3种晶型并对其表征,建立了测定大鼠血浆中米非司酮血药浓度的LC-MS方法,对米非司酮3种晶型在大鼠体内的药动学特性进行比较。方法:借助溶剂结晶、机械化学等不同方法制备米非司酮3种晶型,通过粉末X射线衍射方法、红外光谱法与热重分析法对其表征并测定溶解性。建立用于测定大鼠血浆中米非司酮血药浓度的LC-MS方法,灌胃(ig)给予雌性大鼠米非司酮3种晶型(晶M型、晶W型与晶N型)50 mg·kg-1,测定不同时间点下血药浓度,比较3种晶型在体内的药动学特点。结果:晶型表征结果显示,3种晶型的PXRD、红外等方法检测结果存在明显差异。大鼠ig给予3种晶型后的最大血药浓度(Cmax)分别为(0.82±0.30),(1.40±0.39)和(1.30±0.38)mg·L-1,新晶型(晶W型、晶N型)血药峰浓度较晶M型分别增加了70.0%和57.6%,曲线下面积分别增加了45.7%和42.6%。同时,药物清除率与表观分布容积明显降低。结论:米非司酮晶W型与晶N型在大鼠体内的血药浓度变化与晶M型相比具有明显差异,2种新晶型具有成为优势药用晶型的潜力,可能具有更好的应用前景。Objective:To prepare and characterize three crystal forms of mifepristone by different methods,and to establish a LC-MS method for determination of plasma concentration of mifepristone in rats in order to compare the pharmacokinetic characteristics of the three crystal forms of mifepristone.Methods:Three mifepristone crystals were prepared by solvent crystallization and grinding.The crystals were further characterized by powder X-ray diffraction(PXRD),infrared spectroscopy and thermogravimetric analysis.Also,the solubility of different crystals was determined.An LC-MS method for determination of plasma concentration of mifepristone in rats was established,and applied on female rats which were administered(ig)three forms of mifepristone(crystal M,crystal W and crystal N)at a dose of 50 mg·kg-1.The concentrations of mifepristone in rat plasma were determined and pharmacokinetic properties of the three crystal forms were compared.Results:There is significant difference in the results of PXRD and infrared spectroscopy among three crystals.The maximum concentration(Cmax)of three crystals is(0.82±0.30),(1.40±0.39),and(1.30±0.38)mg·L-1 respectively.Compared with crystal M,the peak plasma concentration of two new crystals,crystal W and crystal N,increased by 70.0%,57.6%,and AUC values increased by 45.7%,42.6%respectively,accompanied with significant reductions of CLz and Vz.Conclusion:There is significant difference in drug plasma concentration between two new crystals and crystal M,indicating that new crystalline drugs have a great potential to be dominant crystalline drug which may have better clinical efficacy.

关 键 词：米非司酮 多晶型药物 避孕 药动学 液质联用 

分 类 号：R932[医药卫生—生药学]