伊曲康唑4种异构体在大鼠体内的药代动力学比较
Stereoselective pharmacokinetics of itraconazole enantiomers in rats
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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 mL/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(P<；0.001)。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: To investigate the stereoselective pharmacokinetics of itraconazole enantiomers in rats, four cis-ITR stereoisomers at the dose of 15 mg/kg were administered orally to rats. Blood was collected and single stereoisomer of ITZ and hydroxy-itraconazole(OH-ITZ)were determinated simultaneously by LC-MS/MS. Samples were extracted by protein precipitation with acetonitrile. Durashell HILIC column(100 mm×2. 1 mm, 5. 0 m)was used as the analytical column, while a mixture of solvent A(0. 02% acetic acid and 5 mmol/L ammonium acetate in water)and B(50% acetonitrile and 50% methyl alcohol)was used as the mobile phase. A 5. 5 min binary gradient elution(delivered at 0. 5 mL/min)was performed for the separation. LC-MS/MS was performed in positive ion mode with multiple reactions monitoring(MRM). The pharmacokinetic parameters of itraconazole enantiomers after the administration were estimated as follows: the plasma levels and AUC0-∞ of OH-(2S, 4R, 2R)-ITZ and OH-(2S, 4R, 2S)-ITZ were higher than those of OH-(2R, 4S, 2R)-ITZ and OH-(2R, 4S, 2S)-ITZ(P< 0. 001). At the same time, female rats exhibited greater cmax, t1/2, AUC0-∞ than male rats, and the absorption of male rats was more rapid than those of females. The findings indicate significant stereoselective differences in the pharmacokinetic parameters of itraconazole enantiomers and gender difference in rats.
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Keywords:
- itraconazole /
- enantiomers /
- stereoselectivity /
- LC-MS/MS /
- pharmacokinetics /
- gender difference
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