【摘 要】
：
目的 探讨抗癫痫新药氯桂丁胺经肝脏药物代谢酶系转化的酶促动力学特征,为临床药物代谢动力学研究制定合理的给药方案提供实验依据.方法 差速离心法分离制备肝微粒体,Bradford法测定微粒体蛋白含量,高效液相色谱法(HPLC-UV)检测氯桂丁胺及其主要代谢物在肝微粒体孵育液中的浓度,Lineweaver-Burke法计算体外代谢的酶促反应动力学参数.结果 在大鼠肝微粒体温孵及辅酶NADPH存在条件下,
【机 构】
：
北京大学医学部基础医学院药理学系,北京市海淀区学院路38号,100191
【出 处】
：
第十届全国药物和化学异物代谢学术会议暨第三届国际ISSX/CSSX联合学术会议
论文部分内容阅读
目的 探讨抗癫痫新药氯桂丁胺经肝脏药物代谢酶系转化的酶促动力学特征,为临床药物代谢动力学研究制定合理的给药方案提供实验依据.方法 差速离心法分离制备肝微粒体,Bradford法测定微粒体蛋白含量,高效液相色谱法(HPLC-UV)检测氯桂丁胺及其主要代谢物在肝微粒体孵育液中的浓度,Lineweaver-Burke法计算体外代谢的酶促反应动力学参数.结果 在大鼠肝微粒体温孵及辅酶NADPH存在条件下,氯桂丁胺原形药色谱峰(4.9 min)之前可见三个代谢物的色谱峰,其保留时间分别为4.2 min (M1)、3.0 min (M2)和3.5 min (M3),并与前期研究中观察到的大鼠血浆及尿液中的代谢物色谱峰保留时间一致.原形药在大鼠肝微粒体中的酶促反应动力学参数分别为：米氏常数Km 14.277 μg/mL,最大反应速率Vmax 15.8228 nmol/min/m8蛋白,消除半衰期为48.53 min.温孵至10、20、60及120 min时,代谢百分率分别为20.88±1.82％、25.13±2.95％、59.63±3.52％及81.93±3.60％.原形药在犬肝微粒体中消除半衰期为16.09 min,温孵至10、20、60及120 min时,原形药的代谢百分率分别为50.02±6.40％、71.32±7.93％、97.02±0.26％及99.08±0.69％.代谢物M1、M2、M3在大鼠肝微粒体中分别占原形药代谢消除率的11.46％、26.89％、60.31％,而在犬则分别占4.89％、69.83％、26.28％.结论 氯桂丁胺原形药在体外可经肝微粒体转化生成三种代谢物,其酶促动力学在犬与大鼠之间具有显著种属差异性,即犬代谢消除较之大鼠快速而完全.尚需对参与代谢物生成的药酶及可能的药物间相互作用进行考察和确证.
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