Prakash C, Jajoo H K, Blair I A, Mayol R F
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.
J Chromatogr. 1989 Sep 1;493(2):325-35. doi: 10.1016/s0378-4347(00)82738-3.
Commercially available chiral columns were unable to provide adequate resolution of enantiomers of the antiarrhythmic drug encainide or its major metabolites. The homochiral derivatizing agent, (-)-menthyl chloroformate, was found to react at the tertiary piperidine nitrogen of racemic encainide providing two menthyl carbamate diastereomers. The individual diastereomers could be separated with baseline resolution on normal-phase high-performance liquid chromatography on a silica column. Structures of the derivatives were confirmed by electron impact mass spectrometry and 1H NMR spectroscopy. The method was adapted for the chiral analysis of the major metabolites of encainide. The limit of sensitivity for racemic encainide was 10 ng on column and it was possible to detect a mixture containing (+)- and (-)-encainide in a ratio of 1:99. Preliminary studies indicated that (-)-encainide was O-demethylated to a greater extent than the (+)-enantiomer by rat liver microsomes.
市售的手性柱无法充分分离抗心律失常药物恩卡尼及其主要代谢物的对映体。发现手性衍生化试剂（-）-氯甲酸薄荷酯能与外消旋恩卡尼的叔哌啶氮发生反应，生成两种氨基甲酸薄荷酯非对映体。在硅胶柱上采用正相高效液相色谱法可实现各非对映体的基线分离。通过电子轰击质谱和1H核磁共振光谱对衍生物的结构进行了确证。该方法适用于恩卡尼主要代谢物的手性分析。外消旋恩卡尼的检测限为柱上10 ng，能够检测出比例为1:99的（+）-和（-）-恩卡尼混合物。初步研究表明，大鼠肝微粒体对（-）-恩卡尼的O-去甲基化程度高于（+）-对映体。
