中药单体小白菊内酯的大鼠血浆稳定性及其药动学研究

Evaluation of plasma stability and pharmacokinetics of parthenolide in rats with LC-MS/MS analysis

小白菊内酯是小白菊(Tanacetum parthenium)中的主要活性成分,具有抗炎和抗癌的药理活性。本研究首先建立了一种专属、灵敏、准确的大鼠血浆中小白菊内酯浓度定量的LC-MS/MS检测方法,采用一步液-液萃取法从大鼠血浆中提取待测物及内标,以水-甲醇为流动相系统对待测物进行分离。标准曲线范围为2~128ng·mL^(-1),精密度、准确度均符合要求,并且提取回收率较高。利用此检测方法对体外放置大鼠血浆样品中小白菊内酯的稳定性进行了考察,结果显示高、中、低3个浓度的小白菊内酯在30 min后均有超过15%的分解,表明其在大鼠血浆中稳定性较差。体内药动学实验分别静脉给予大鼠20、40及80mg·kg^(-1)的小白菊内酯,药动学参数显示其在大鼠体内消除较快,半衰期小于90min。高剂量80mg·kg^(-1)给药组初始浓度也仅为138.86±21.07ng·mL^(-1),并且药时曲线下面积与给药剂量非等比例增加。本研究结果为进一步开发小白菊内酯成为抗肿瘤药物提供了重要的药动学信息。

Parthenolide is a sesquiterpene lactone derived from the plant feverfew （Tanacetum parthenium） that possesses multiple anti-inflammatory and anti-cancer properties. A specific, sensitive, accurate and precise LC-MS/MS method was developed and validated in the quantitative analysis of parthenolide in rat plasma. A liquid-liquid extraction method was used to separate the analyte and the internal standard （IS, costunolide） from plasma. A water-methanol mobile phase system was utilized in the gradient chromatographic separation. The calibration curve with good linearity （rE〉 0.99） was established between 2 and 128 ng ·mL^-1 with accuracy and precision within acceptable limits at different QC levels. High extraction recovery was achieved for both parthenolide （89.55%-95.79%） and IS （96.87%）. Based on this LC-MS/MS method, the plasma stability and pharmacokinetics of parthenolide were assessed in rats, Parthenolide was proved to be very unstable in rat plasma, and was distributed and eliminated quickly in vivo, with a half-life less than 90 min. A high dose of parthenolide （80 mg.kg 1） resuked in a very low initial concentration （138.86 -21.07 ng·mL^-1）. The systemic exposure of parthenolide （area under the curve） increased disproportionally from 40 mg ·kg^-1 dose group to 80 mg·kg^-1 dose group. The present study may provide helpful information for the development ofparthenolide as a drug candidate.