Turgeon J, Paré J R, Lalande M, Grech-Bélanger O, Bélanger P M
School of Pharmacy, Laval University, Ste-Foy, Quebec, Canada.
Drug Metab Dispos. 1992 Sep-Oct;20(5):762-9.
Urine samples from control and mexiletine-treated human subjects or rabbits (test group) were collected and passed through an ion exchange resin to isolate polar compounds. Methanolic eluates from control and test urines were analyzed by TLC. Exposure to p-dimethylaminocinnamaldehyde gave an additional intense pink band at Rt 0.40-0.45 in TLC analysis of test urine eluate when compared to control urine eluate. Non-exposed silica at this Rt was scraped and metabolites were extracted with methanol. Hydrolysis of this methanolic extract at 100 degrees C with hydrochloric acid released mexiletine. GC/MS and fast atom bombardment mass spectrometry analyses of nonhydrolyzed methanolic extracts evidenced the presence of two conjugated metabolites of mexiletine, namely, N-hydroxymexiletine glucuronide and mexiletine alcohol glucuronide. Synthetic compounds corresponding to these metabolites were obtained and spectra compared with those of isolated metabolites from urine. Definite structure assignment of N-hydroxymexiletine glucuronide was obtained from NMR spectrometry which confirmed the structure to be a hydoxylamine glucuronide (N-O-C link) and showed that the glycoside moiety was in the beta configuration. Thus, it is proposed that N-hydroxymexiletine glucuronide corresponds to mexiletine acid-labile conjugate and represents a major metabolic pathway in the disposition of mexiletine.
收集来自对照和美西律治疗的人类受试者或兔子（试验组）的尿液样本，并使其通过离子交换树脂以分离极性化合物。对照尿液和试验尿液的甲醇洗脱液通过薄层层析法进行分析。与对照尿液洗脱液相比，在试验尿液洗脱液的薄层层析分析中，用对二甲基氨基肉桂醛处理后在保留时间0.40 - 0.45处出现了一条额外的强烈粉红色条带。在该保留时间处未曝光的硅胶被刮下，代谢物用甲醇提取。该甲醇提取物在100℃用盐酸水解后释放出美西律。对未水解的甲醇提取物进行气相色谱/质谱联用分析和快原子轰击质谱分析，证明存在美西律的两种共轭代谢物，即N - 羟基美西律葡糖苷酸和美西律醇葡糖苷酸。获得了与这些代谢物对应的合成化合物，并将其光谱与从尿液中分离出的代谢物的光谱进行比较。通过核磁共振光谱法确定了N - 羟基美西律葡糖苷酸的结构，证实其结构为羟胺葡糖苷酸（N - O - C键），并表明糖苷部分为β构型。因此，有人提出N - 羟基美西律葡糖苷酸对应于美西律的酸不稳定共轭物，并且是美西律处置过程中的主要代谢途径。
