State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, 999078, Macao.
J Pharm Biomed Anal. 2014 Jan;88:269-77. doi: 10.1016/j.jpba.2013.08.042. Epub 2013 Sep 7.
Many chiral drugs are used as the racemic mixtures in clinical practice. The occurrence of enantioselectively pharmacological activities calls for the development of enantiospecific analytical approaches during pharmacokinetic studies of enantiomers. Sample preparation plays a key role during quantitative analysis of biological samples. In current study, a rapid and reliable online solid phase extraction-chiral high performance liquid chromatography-tandem mass spectrometry (online SPE-chiral LC-MS/MS) method was developed for the simultaneously enantiospecific quantitation of (+)-trans-khellactone (dTK), (+/-)-cis-khellactone (d/lCK), (+/-)-praeruptorin A (d/lPA), (+/-)-praeruptorin B (d/lPB) and (+)-praeruptorin E (dPE), the main active angular-type pyranocoumarins (APs) in Peucedani Radix (Chinese name: Qian-hu) or the major metabolites of those APs, in rat plasma. The validation assay results described here show good selectivity and enantiospecificity, extraction efficiency, accuracy and precision with quantification limits (LOQs) of 2.57, 1.28, 1.28, 1.88, 4.16, 4.16 and 4.18ngmL(-1) for dTK, lCK, dCK, dPA, dPB, lPB and dPE, respectively, while lPA was not detected in rat plasma due to the carboxylesterase(s)-mediated hydrolysis. In addition, the validated system was satisfactorily applied to characterize the pharmacokinetic properties of those components in normal and chronic obstructive pulmonary disease (COPD) rats following oral administration of Qian-hu extract. dCK and lCK were observed as the main herb-related compounds in plasma. Enantioselectively pharmacokinetic profiles occurred for dCK vs lCK, dPA vs lPA, and dPB vs lPB in either normal or COPD rats. The proposed whole system is expected to be a preferable analytical tool for in vivo study of chiral drugs, in particular for the characterization of enantioselectively pharmacokinetic profiles.
许多手性药物在临床实践中被用作外消旋混合物。对映选择性药理活性的出现要求在对映异构体的药代动力学研究中开发对映体特异性分析方法。样品制备在生物样品的定量分析中起着关键作用。在本研究中，建立了一种快速可靠的在线固相萃取-手性高效液相色谱-串联质谱法（在线 SPE-手性 LC-MS/MS），用于同时对映选择性定量测定 (+)-反式金合欢内酯（dTK）、（±）-顺式金合欢内酯（d/lCK）、（±）-白屈菜丙素（d/lPA）、（±）-白屈菜乙素（d/lPB）和（+）-白屈菜丙素 E（dPE），这些是 Peucedani Radix（中文名称：前胡）中的主要活性角型吡喃香豆素（APs）或这些 APs 的主要代谢物，在大鼠血浆中。这里描述的验证测定结果表明，该方法具有良好的选择性和对映体特异性、提取效率、准确性和精密度，定量限（LOQ）分别为 2.57、1.28、1.28、1.88、4.16、4.16 和 4.18ngmL(-1)，用于 dTK、lCK、dCK、dPA、dPB、lPB 和 dPE，而 lPA 由于羧酯酶介导的水解而未在大鼠血浆中检测到。此外，该经验证的系统满意地应用于表征口服前胡提取物后正常和慢性阻塞性肺疾病（COPD）大鼠中这些成分的药代动力学特性。dCK 和 lCK 被观察为血浆中主要的草药相关化合物。在正常或 COPD 大鼠中，dCK 与 lCK、dPA 与 lPA 和 dPB 与 lPB 均发生对映选择性药代动力学特征。所提出的整个系统有望成为手性药物体内研究的首选分析工具，特别是用于表征对映选择性药代动力学特征。
