Du Yueying, Luo Linda, Sun Shuo, Jiang Zhen, Guo Xingjie
School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenhe District Shenyang, Liaoning, 110016, China.
Anal Bioanal Chem. 2017 Nov;409(27):6315-6323. doi: 10.1007/s00216-017-0551-z. Epub 2017 Aug 29.
Miconazole has one chiral center, and consists of two enantiomers. In this study, a novel chiral liquid chromatography-tandem mass spectrometry method was developed for enantioselective separation and determination of miconazole in rat plasma. For the first time, the enantioselective pharmacokinetics of miconazole was investigated by the current method. Firstly, attempts were made to separate the enantiomers in reversed-phase mode with a mobile phase that was mass spectrometry compatible. Baseline separation was achieved on a Chiralpak IC column with a mobile phase composed of acetonitrile and aqueous ammonium hydrogen carbonate (5 mM; 80:20, v/v). Data were acquired in multiple reaction monitoring mode with positive electrospray ionization by triple-quadrupole mass spectrometry. Then, overall method validation regarding the linearity, accuracy, precision, extraction recovery, matrix effect, and stability of each enantiomer was performed, and acceptable results were obtained for all of these. Finally, the method developed was applied in an enantioselective pharmacokinetic study of miconazole enantiomers in rats after oral administration of racemic miconazole at doses of 5 and 10 mg/kg. The results demonstrated that (-)-(R)-miconazole had a higher concentration than (+)-(S)-miconazole in plasma, with a ratio of 1.3-1.7 for both doses. This is the first experimental evidence of enantioselective behavior of miconazole in vivo, and provides a reference for clinical practice and encourages further research into miconazole enantioselective metabolism and drug interactions. Graphical Abstract A stereoselective pharmacokinetic study of the miconazole enantiomers was investigated using a novel chiral liquid chromatography-tandem mass spectrometry method. Baseline separation was achieved on Chiralpak IC column, and Chiralcel OJ column was used to collect single enantiomer. A significant difference between the two enantiomers was observed in view of the plasma concentration.
咪康唑有一个手性中心，由两种对映体组成。本研究建立了一种新型手性液相色谱 - 串联质谱法，用于大鼠血浆中咪康唑对映体的选择性分离和测定。首次采用该方法研究了咪康唑的对映体选择性药代动力学。首先，尝试在反相模式下使用与质谱兼容的流动相分离对映体。在Chiralpak IC柱上，以乙腈和碳酸氢铵水溶液（5 mM；80:20，v/v）组成的流动相实现了基线分离。通过三重四极杆质谱在正电喷雾电离的多反应监测模式下采集数据。然后，对各对映体的线性、准确性、精密度、提取回收率、基质效应和稳定性进行了整体方法验证，所有这些均获得了可接受的结果。最后，将所建立的方法应用于大鼠口服5和10 mg/kg消旋咪康唑后咪康唑对映体的对映体选择性药代动力学研究。结果表明，血浆中（-）-（R）-咪康唑的浓度高于（+）-（S）-咪康唑，两种剂量下的比值均为1.3 - 1.7。这是咪康唑在体内对映体选择性行为的首个实验证据，为临床实践提供了参考，并鼓励对咪康唑对映体选择性代谢和药物相互作用进行进一步研究。图形摘要 使用新型手性液相色谱 - 串联质谱法研究了咪康唑对映体的立体选择性药代动力学。在Chiralpak IC柱上实现了基线分离，并使用Chiralcel OJ柱收集单一对映体。在血浆浓度方面观察到两种对映体之间存在显著差异。
