伊曲康唑4种异构体在大鼠体内的药代动力学比较

发布时间：2018-04-01 22:07

  本文选题：伊曲康唑　切入点：异构体　出处：《中国药科大学学报》2015年03期

【摘要】：采用LC-MS/MS法研究伊曲康唑4种异构体在大鼠体内的药代动力学差异。大鼠分别灌胃伊曲康唑4种异构体后,用LC-MS/MS法测定血浆中伊曲康唑4种异构体的代谢及主要代谢产物羟基伊曲康唑的生成情况。采用乙腈直接沉淀蛋白,色谱柱为Durashell HILIC柱(100 mm×2.1 mm,5.0 m),流动相中有机相为甲醇-乙腈(1∶1),水相为含5 mmol/L乙酸铵和0.2%乙酸的超纯水,以0.5 m L/min的流速进行梯度洗脱,总洗脱时间为5.5 min。扫描方式为选择反应监测(MRM),采用正离子方法检测。大鼠单次灌胃给予15 mg/kg伊曲康唑4种不同异构体后,2S,4R,2R型伊曲康唑和2S,4R,2S型伊曲康唑在大鼠体内的羟基代谢物的生成量明显高于(2R,4S,2R)型伊曲康唑和(2R,4S,2S)型伊曲康唑(P0.001)。此外,伊曲康唑在大鼠中存在明显的雌雄差异,雌性大鼠体内的峰浓度(cmax)和药时曲线下面积(AUC0-∞)明显高于雄鼠,半衰期(t1/2)明显长于雄鼠,消除较雄鼠慢。通过检测伊曲康唑4种异构体原药及相应的羟基代谢物在大鼠体内的经时过程,表明不同异构体在大鼠体内的药代动力学行为存在明显的代谢差异和性别差异。
[Abstract]:The pharmacokinetics of four isomers of itraconazole in rats was studied by LC-MS/MS. The metabolism of four isomers of itraconazole and the formation of its main metabolite hydroxyitraconazole in plasma were determined by LC-MS/MS method. The protein was precipitated by acetonitrile. The chromatographic column was Durashell HILIC column (100mm 脳 2.1mm), the organic phase in the mobile phase was methanol-acetonitrile (1: 1), the water phase was ultrapure water (containing 5 mmol/L ammonium acetate and 0.2% acetic acid), and the gradient elution was carried out at the flow rate of 0.5 m L/min. The total elution time was 5.5 mins. The scanning method was selected to monitor the reaction and detected by positive ion method. Rats were given 4 different isomers of itraconazole for 15 mg/kg by single gavage. The production of hydroxyl metabolites was significantly higher than that of itraconazole and itraconazole (P 0.001). Itraconazole was significantly different between male and female in rats. The peak concentration of itraconazole in female rats was significantly higher than that in male rats, and the area under the drug time curve (AUC0- 鈭，

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