N,N-二甲氨基甲酸5-(1,3,3-三甲基吲哚满)酯及其代谢产物在大鼠离体肝脏中的代谢动力学

Pharmacokinetics of 5-(1, 3, 3-trimethylindolinyl)N,N- dimethyl carbamate and its metabolites inthe isolated perfused rat livers

利用大鼠肝脏灌流技术研究了N,N-二甲氨基甲酸5-(1,3,3-三甲基吲哚满)酯(TMDMC)及其代谢产物在大鼠离体肝脏中的代谢动力学,TMDMC在改良的灌流液中作循环式灌流,于不同时间留取少量灌流液,用高效液相色谱(HPLC)作药物的定量分析,结果显示其在离体灌流肝脏中的清除模型符合两相消除模型,动力学参数表明,TMDMC在肝内的分布较快,其分布半衰期仅为4min,肝脏分布容积为102.4 ml,清除率是0.67ml·min^(-1),清除比率为0.027.灌流2h时,其浓度已下降了73％.与此同时,TMDMC的代谢产物逐渐生成,其中以产物Ⅲ的生成量最大,其最高生成浓度(C_(max))为447.1 μg·ml^(-1),2 h产物Ⅲ的生成总量已达TMDMC灌流量的25.6％.而代谢产物Ⅱ,Ⅵ的生成较少,其C_(max)分别是20.4μg·ml^(-1)和20.7μg·ml^(-1).

The pharmacokinetics of 5 (1, 3, 3-trimethylindolinyl) N, N-dimethyl carbamate (TMDMC) and its metabolites were studied in the isolated perfused rat livers. The livers were perfused with TMDMC dissolved in a modified Krebs-Henseleit solution. The concentration of TMDMC and its metabolites from the perfusates were measured by HPLC. The results showed that the pharmacokinetics of TMDMC in the perfused liver corresponded to the two-compartment model. TMDMC in the perfusate was quickly eliminated as the perfusate passed throughthe liver with a t1 /2 a of 4 min and a Ⅵ of 102 ml in 20 min. By 2 h perfusion, the concentration of TMDMC reduced 73%. In the meanwhile, the metabolites, especially metabolite Ⅲ , were gradually formed. The maximal concentration of metabolite Ⅲ was about 477 μg·ml-1. The results suggest that the liver is one of the main organs which metabolize TMDMC.