~1H核磁共振谱直接观测N，N－二甲氨基甲酸－间－（2－二甲氨基）乙氧基苯酯在原位灌流大鼠肝脏中的代谢

应用高分辨Ｈ核磁共振谱（ＨＮＭＲ）直接观测Ｎ，Ｎ－二甲氨基甲酸－间－（２－二甲氨基）乙氧基苯酪（ＤＭＤＭＣ）在原位灌流大鼠肝脏中的代谢产物和代谢动力学过程。灌流不同时间采集样本在４００ＭＨｚＮＭＲ谱仪上直接用选择自旋翻转回波ＨＮＭＲ法进行定性和定量分析．ＤＭＤＭＣ在灌流大鼠肝脏中的主要代谢产物是羟基ＤＭＤＭＣ和Ｎ－去甲基ＤＭＯＭＣ，其消除半衰期为１１２ｍｍ．羟基ＤＭＤＭＣ的生成量最大，其最高生成值ｒｍａｘ为０．４９，Ｎ－去甲基ＤＭＤＭＣ的ｒｍａｘ为０．２６当大鼠用苯巴比妥（８０ｍｇ·ｋｇ－１·ｄ－１）预处理４ｄ后，ＤＭＤＭＣ在灌流大鼠肝脏中的代谢消除加快。消除半衰期缩短为５４ｍｈ。同时代谢产物的生成和转化速度增加结果表明。ＤＭＤＭＣ在灌流大鼠肝脏中的主要代谢途径是氨基甲酸酯侧链的氧化代谢。苯巴比妥预处理可以加速ＤＭＤＭＣ在大鼠肝脏中的氧化代谢过程．

Metabolism of[m-(2-dimethylamino)] ethoxy phenyl-N,N-dimethylcarbamate hydrochloride monitored by Hnuclear magnetic resonance spectroscopy in in situ perfused rat liver

High-resolution H nudear magne-tic resonance(NMR) spectroscopy at 400 MHz hadbeen used to monitor the metabolism of m-(2-dimethylamino)] ethoxy phenyl-N, N-dimethylcarbamate hydrochloride (DMDMC), a newanticholinesterase drug, by the in situ perfused rat liv-er. Samples of perfusate removed at various times dur-ing the perfusion were detected qualitatively andquantitatively by the selective spin inversion recoveryecho i H NM R technique. These NM R spectra showedresonances from DMDMC and its metabolites. as wellas those from organic metabolites released from the liv-er after addition of DMDMC (150 mg . L-1). Of theresonances in the spectra, four singlets, at 2.64, 2.86,2.94 and 3.00 ppm, were likely to be most useful foridentification and quantification of the parent drugand its metabolites because they were well-resolvedand lacked multiplet structure. These singlets were cor-responding to two N-CH3 groups of the carbamatechain of these compounds. The major metabohtes wereidentified as hydroxylated DMDMC and N-demethy-lated DMDMC. Accordingly. these resonances wereused to monitor the disappearance of DMDMC andthe forfnation of its metabolites. The elimination halflife of the parent drug was 112 min. The relativemaximal fonnation of hydroxylated DMDMC was0.49, and Ndemethylated DMDMC was 0.26. Follow-ing pretreatment with phenobarbital for 4 d (80 mg .kg-1 . d-1), the metabolic rate of DMDMC wasmarkedly increased in the liver, with an eliminationhalf life of 54 min. In the meanwhile. the forniationrates of the two metabolites in the perfused liver werealso increased. The results indicated that oxidation ofthe side chain carbamate is the major fate of DMDMCin the in situ perfused rat liver and this metabolic reac-tion was stimulated in livers from rats pretreated withphenobarbital .