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中国临床药理学与治疗学 ›› 2009, Vol. 14 ›› Issue (11): 1269-1274.

• 基础研究 • 上一篇    下一篇

头孢妥仑测定方法的建立及胆汁排泄机制研究

张庆颢, 孟强, 刘琦, 王长远, 梅林, 孙慧君, 刘克辛   

  1. 大连医科大学药学院临床药理教研室, 大连116044, 辽宁
  • 收稿日期:2009-06-24 修回日期:2009-11-05 发布日期:2020-10-26
  • 作者简介:张庆颢, 男, 硕士, 研究方向:药代动力学。Tel:15001383298 E-mail:zqh first@163.com; 孟强, 女, 硕士, 助教, 研究方向:药代动力学。Tel:13304097535 E-mail:mengq531@yahoo.cn;张庆颢, 孟强同为第一作者

Construction of determination of cefditoren and the investigation of mechanism of biliary excretion

ZHANG Qing-hao, MENG Qiang, LIU Qi, WANG Chang-yuan, MEI Lin, SUN Hui-jun, LIU Kexin   

  1. Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, Liaoning, China
  • Received:2009-06-24 Revised:2009-11-05 Published:2020-10-26

摘要: 目的:建立高效液相色谱内标法测定大鼠血浆、胆汁、尿液中头孢妥仑含量, 阐明多药耐药相关蛋白2(Mrp2) 是否与头孢妥仑胆汁排泄有关。方法:用4-二甲氨基安替比林作内标。色谱柱为Capcell pak C18 UG120 (4.6 mm ×250 mm,5 μm), 流动相为0.1 %醋酸铵-甲醇(67:33, VV), 流速为0.8 mL/min, 进样量为25 μL;用肝灌流法探讨头孢妥仑是否经Mrp2 转运。设立对照组(头孢妥仑1 μmol/L) 和实验组(头孢妥仑1 μmol/L 加Mrp2 抑制剂丙磺舒20 μmol/L), 在设定时间点于灌流的大鼠肝脏收集出口灌流液和胆汁样品, 高效液相色谱法测定样品中头孢妥仑含量, 考察实验组和对照组中肝摄取率和胆汁累积排泄率的差异。结果:血浆样品中头孢妥仑在0.1 ~ 4 μg/mL 范围内、胆汁样品中头孢妥仑在0.1 ~ 5 μg/mL 范围内、尿液样品中头孢妥仑在0.1 ~ 5 μg/mL 范围内线性关系良好。回收率为85 %~ 115 %, 日内、日间RSD 均小于13.5 %。实验组和对照组相比, 肝摄取率变化无统计学意义上的差别;实验组中, 肝灌流25 min 后, 头孢妥仑胆汁累积排泄率减少至对照组的40.0 %。结论:本方法经济、简单、灵敏、快速, 可用于头孢妥仑血浆、胆汁、尿液样品中药物浓度检测和药物代谢动力学研究;头孢妥仑是Mrp2 的底物, Mrp2 与头孢妥仑的胆汁排泄有关。

关键词: 头孢妥仑, 高效液相色谱法, 肝灌流, 多药耐药相关蛋白2

Abstract: AIM: To develop a high-performance liquid chromatography internal standard method for determining of cefditoren in the rat plasma, bile and urine, and to clarify the relation between multidrug resistance- associated protein 2 (Mrp2) and biliary excretion of cefditoren using perfused rat livers. METHODS: 4-dimethylaminoantipyrine was used as the internal standard.Chromatographic separation was performed on a C18 UG 120 column (4.6 mm ×250 mm, 5 μm) and mobile phase was composed of 0.1 % ammonium acetate and methyl alcohol (67:33, V/V). The flow rate was 0.8 mL/min and 25 μL of mixture was injected.Perfused rat livers were performed to investigate whether cefditoren was transported via Mrp2. We established the control (cefditoren 1 μmol/L) and experimental group (cefditoren 1 μmol/L added the inhibitor of Mrp2-probenecid, 20 μmol/L).Perfusate samples and bile were collected at setting times.Cefditoren was determined by HPLC.We compared the hepatic extraction ratio and cumulative biliary excretion rates in control and experimental groups. RESULTS: The concentration range of cefditoren was 0.1 -4 μg/mL in plasma, 0.1 -5 μg/mL in bile and in urine, with good linearity.The relative recovery was 85 %- 110 %.The intra- and inter-day RSD were <13.5 %. The hepatic extraction ratio showed no statistically significant differences, whereas cumulative biliary excretion rates were significantly reduced to 40.0 % compared to control over 25 min in experimental group. CONCLUSION: It can be used for the determination of cefditoren concentration in plasma, bilary and urinary samples and for pharmacokinetic study since it is economic, simple, sensitive and fast method.Cefditoren is the substrate of Mrp2, which is related with biliary excretion of cefditoren.

Key words: cefditoren, HPLC, perfused livers, multidrug resistance-associated protein 2

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