【作者】 宋月林； 景王慧； 周瑞娜； 吴文进； 燕茹； 王一涛；

【Author】 Song Yuelin1,Jing Wanghui1,Zhou Ruina1,Wu Wenjin1,Yan Ru1,Wang Yitao1,2 (1. Institute of Chinese Medical Sciences,University of Macau,Macau; 2. Peking University of Chinese Medicine,Beijing)

【机构】 澳门大学中华医药研究院； 北京中医药大学；

【摘要】 目的利用chiral LC/MS/MS首次研究比较白花前胡中主要香豆素类成分白花前胡甲素((±)-praeruptorin A,PA)及其手性对映异构体白花前胡丙素((+)-praeruptorin A,dP A)和(-)-praeruptorin A(lPA)的体内药动学及其转化。方法雄性SD大鼠分别静脉注射白花前胡甲素(4mg/kg)及其手性对映异构体(分别2mg/kg),利用手性高效液相色谱-质谱联用系统,以MRM对血浆样品进行定量,以EMS-IDA-EPI进行代谢产物鉴定。利用WinNonlin 5.1软件,采用非房室模型进行药动学参数的计算。结果建立了适合于PA,dPA及其光学对映体lPA的大鼠体内药动学研究的定量方法;静注PA与dPA后,dPA在大鼠体内快速分布、消除。静注PA与lPA后,大鼠血浆中均无法检测到lPA。三者在体内均能产生3个C-3′当归酰基单氧化产物,PA和lPA同时能产生2个C-4′水解产物。结论 dPA与lPA体内药动学过程显示出手性差异性,该差异的产生可能是由血浆中羧酸酯酶对于对映异构体催化活性的不同引起。更多还原

【Abstract】 OBJECTIVE To investigate and compare, for the first time, the pharmacokinetic profiles and in vivo biotransformation of (±)-praeruptorin A (PA), the main coumarin and the chemical marker of Qianhu (dried root of Peucedanum praeruptorum Dunn), and its dextrorotatory (dPA) and levorotatory (lPA) enantiomers using chiral-LC-MS/MS. METHODS PA (4 mg/kg) and its individual enantiomers (each 2 mg/kg) were administered intravenously to the rat. Blood samples were obtained at appropriate time intervals. dPA and/or lPA in the plasma were quantitatively determined by MRM and structural identification of metabolites were carried out by EMS-IDA-EPI. Pharmacokinetic parameters were obtained with WinNonlin 5.1 software using non-compartmental analysis. RESULTS An chiral- LC-MS/MS method was developed for pharmacokinetic study of (±)-praeruptorin A , (+)-praeruptorin A and (-)-praeruptorin A in the rat. After intravenous administration of dPA and PA, dPA exhibited extensive distribution, rapid elimination and similar systemic exposure. However, lPA was not detectable after an intravenous dosage of either form (lPA or PA). All PA, dPA and lPA generated 3 oxidative metabolites formed from oxidation of C-3′ angeloyloxy group; PA and lPA gave 2 additional metabolites formed from hydrolysis at C-4′ position. CONCLUSION dPA and lPA exhibited chiral difference in their pharmacokinetic profile in the rat. Chiral discrimination in hydrolysis of PA enantiomers by carboxylesterases in the rat plasma might exist and account for the pharmacokinetic difference observed.更多还原