苦地丁中紫堇灵和乙酰紫堇灵在急性肺损伤大鼠体内的药代动力学研究

Pharmacokinetic Study of Corynoline and Acetylcorynoline in LPS-Induced Acute Lung Injury Rats After Oral Administration ofCorydalis Bungeana Turcz Extract

  • 摘要: 目的 研究苦地丁中主要活性成分紫堇灵和乙酰紫堇灵在急性肺损伤大鼠体内的药代动力学研究。方法 建立同时测定大鼠血浆中紫堇灵和乙酰紫堇灵的LC-MS/MS分析方法,血浆样品采用乙腈沉淀蛋白,在C18色谱柱下进行梯度洗脱。离子源为电喷雾离子源,采用多反应离子检测。同时对其专属性、线性及范围、准确度、精密度、稳定性、基质效应进行考察。采用滴鼻LPS诱导急性肺损伤大鼠模型,灌胃428 mg/kg苦地丁提取物后,测定大鼠血浆中紫堇灵和乙酰紫堇灵的血药浓度,采用DAS3.0计算其药代动力参数。结果 紫堇灵和乙酰紫堇灵在0.25~100.0 ng/mL和0.40~160.0 ng/mL之间有较好的线性(R2>0.995);同时批间及批内精密度和准确度、基质效应、回收率以及不同条件下的稳定性均符合要求。与正常组相比,急性肺损伤大鼠体内的紫堇灵暴露水平显著增加(AUC,P<0.01),而乙酰紫堇灵的暴露水平未见明显变化。结论 该方法具有快速、灵敏、准确的特点,可用于苦地丁提取物中紫堇灵和乙酰紫堇灵体内药代动力学研究,同时紫堇灵在急性肺损伤大鼠体内暴露水平显著增加,清除显著减弱。

     

    Abstract: OBJECTIVE To explore the pharmacokinetics of corynoline and acetylcorynoline in LPS induced acute lung injury(ALI) rats after oral administration ofCorydalis bungeana Turcz extract. METHODS LC-MS/MS analytical method was developed and fully validated to determine corynoline and acetylcorynoline in rat plasma. Plasma samples were prepared by acetonitrile precipitation and then separated in a C18 column. The analytes were determined in an ESI source and then by MRM mode. The method was then fully validated by specificity, linearity, precision, accuracy, matrix effect, recovery and stability. Then, a comparative pharmacokinetic study of corynoline and acetylcorynoline in normal and LPS induced acute lung injury rats was performed, following the oral administration ofCorydalis bungeana Turcz extract (428 mg/kg). The plasma samples were then collected and analyzed after oral administration of the extract. Pharmacokinetic parameters were then calculated by the DAS3.0. RESULTS Calibration curves indicated that a desirable linearity (R2>0.995) were found and the linearity range for corynoline was 0.25-100.0 ng/mL, and 0.40-160.0 ng/mL for acetylcorynoline. And the LLOQs were sufficient for quantitative analysis. The precision and accuracy were assessed by intra-batch and inter-batch assays, and the relative standard deviation (RSD) and the accuracy (RE) was all acceptable. The extraction recoveries, matrix effects and stability were also acceptable in this study. The pharmacokinetic study indicated that the AUC(0-t) of corynoline in ALI rats was significantly increased when comparing with control rats. But the systemic exposure of acetylcorynoline was not changed in ALI rats as compared with the normal rats. CONCLUSION The developed LC-MS/MS method is fast, sensitive, accuracy and can be used in the pharmacokinetic study of corynoline and acetylcorynoline after oral administration ofCorydalis bungeana Turcz extract in rats. And the exposure of corynoline was significantly increased, while the clearance was significantly decreased in the ALI rats as compared with the control rats.

     

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