Zhou Ting, Zeng Jing, Liu Shan, Zhao Ting, Wu Jie, Lai Wenshi, He Mingzhi, Xu Beining, Qu Shanshan, Xu Ling, Tan Wen
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, 510006, China; Pre-incubator for Innovative Drugs and Medicine, South China University of Technology, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, South China University of Technology, Guangzhou 510006, China.
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, 510006, China.
J Chromatogr B Analyt Technol Biomed Life Sci. 2015 Oct 1;1002:218-27. doi: 10.1016/j.jchromb.2015.08.020. Epub 2015 Aug 28.
The chiral inversion has been a concerned issue during the research and development of a chiral drug. In this study, a sensitive chiral liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for determination of salbutamol enantiomers in human plasma and urine. The chiral inversion mechanism of R-salbutamol was fully investigated for the first time by studying the effects of physicochemical factors, including pH, temperature and time. A fitted model to predict the chiral inversion ratio of R-salbutamol was proposed using a Box-Behnken design. All the samples were separated on an Astec Chirobiotic T column and detected by a tandem mass spectrometer in multiple reaction monitoring mode. Lower limit of quantification of 0.100ng/mL was achieved under the optimized conditions. The method was fully validated and successfully applied to the clinical pharmacokinetic study of R-salbutamol in healthy volunteers. Chiral inversion of R-salbutamol to S-salbutamol has been detected in urine samples. The results indicated that pH and temperature were two dominant factors that caused the chiral inversion of R-salbutamol, which should be taken into consideration during the analysis of chiral drugs. The chiral inversion of R-salbutamol determined in this study was confirmed resulted from the gastric acid in stomach rather than caused by the analysis conditions. Moreover, the calculated results of the fitted model matched very well with the enantioselective pharmacokinetic study of R-salbutamol, and the individual difference of the chiral inversion ratio of R-salbutamol was related to the individual gastric environment. On the basis of the results, this study provides important and concrete information not only for the chiral analysis but also for the metabolism research of chiral drugs.
在手性药物的研发过程中，手性转化一直是一个备受关注的问题。在本研究中，开发了一种灵敏的手性液相色谱 - 串联质谱（LC-MS/MS）方法，用于测定人血浆和尿液中的沙丁胺醇对映体。通过研究包括pH、温度和时间在内的物理化学因素的影响，首次全面研究了R-沙丁胺醇的手性转化机制。使用Box-Behnken设计提出了一个预测R-沙丁胺醇手性转化比率的拟合模型。所有样品在Astec Chirobiotic T柱上分离，并通过串联质谱仪在多反应监测模式下进行检测。在优化条件下，定量下限达到0.100ng/mL。该方法经过充分验证，并成功应用于健康志愿者中R-沙丁胺醇的临床药代动力学研究。在尿液样本中检测到了R-沙丁胺醇向S-沙丁胺醇的手性转化。结果表明，pH和温度是导致R-沙丁胺醇手性转化的两个主要因素，在手性药物分析过程中应予以考虑。本研究中测定的R-沙丁胺醇的手性转化经证实是由胃中的胃酸引起的，而非分析条件所致。此外，拟合模型的计算结果与R-沙丁胺醇的对映选择性药代动力学研究结果非常吻合，且R-沙丁胺醇手性转化比率的个体差异与个体胃部环境有关。基于这些结果，本研究不仅为手性分析，也为手性药物的代谢研究提供了重要而具体的信息。
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