木犀草素及其磺丁基醚-β-环糊精包合物在大鼠体内的药代动力学研究

目的：建立抗肿瘤药物木犀草素靶向制剂在大鼠血浆中的含量测定方法，研究木犀草素及其磺丁基醚-β-环糊精（SBE-β-CD）包合物在大鼠体内的药代动力学。方法：通过灌胃和尾静脉注射2种方式分别给予SD大鼠木犀草素与木犀草素/SBE-β-CD包合物，血浆样品经水浴-液液萃取法处理后，采用高效液相色谱法（HPLC）检测，以香叶木素为内标，采用ZORBAX SB-C₁₈（4.6 mm×250 mm，5 μm）色谱柱，流动相0.2%磷酸溶液-甲醇（48：52），流速1.0 mL·min^-1，检测波长348 nm，使用DAS药代动力学程序进行计算，得到相关药代动力动学参数。结果：木犀草素/SBE-β-CD包合物平均包合率为75.94%；大鼠血浆中木犀草素质量浓度在0.06~13.00 μg·mL^-1范围内线性关系良好；血浆中木犀草素提取回收率为72.19%~86.62%，RSD为5.60%~12.77%。结论：本方法符合方法学验证基本要求，适用于木犀草素在大鼠血浆中的含量测定，可用于药代动力学研究。木犀草素在大鼠体内消除符合二室消除模型，与木犀草素相比，木犀草素/SBE-β-CD包合物达峰时间提前，药-时曲线下面积增大，生物利用度提高。

Objective:To establish an HPLC method for the determination of the concentration of targeted antitumor drugs luteolin in rat plasma,and to study the pharmacokinetics of luteolin and its sulfobutyl ether-β-cyclodextrin(SBE-β-CD)inclusion complex in rat.Methods:SD rats with luteolin and luteolin/SBE-β-CD inclusion complex were given by intragastric administration and intravenous injection in 2 ways,respectively.Plasma samples were pretreated by water bath and liquid-liquid extraction,detected by HPLC,diosmetin was employed as an internal standard.The separation was performed on a ZORBAX SB-C₁₈ (4.6 mm×250 mm,5 μm) column and the mobile phase consisted of 0.2% H₃PO₄ -methanol (48:52)at a flow rate of 1.0 mL·min^-1,and the detection wavelength was 348 nm.The DAS pharmacokinetic program was used to calculate the relevant pharmacokinetic parameters.Results:The average entrapment efficiency of luteolin/SBE-β-CD inclusion complex was 75.94%.Luteolin in rat plasma had a good liner relationship in concentration range in 0.06-13.00 μg·mL^-1.The extraction recovery(n=5) and the RSD of luteolin were within 72.19%-86.62% and 5.60%-12.77%,respectively.Conclusion:The method conforms to the basic requirements of methodology validation and is suitable for the determination of luteolin in rat plasma and can be used for pharmacokinetic studies.The elimination of luteolin in rats conformed to two compartment model elimination.Compared with luteolin,the T_max advance and the AUC increase which resulted in an improved bioavailability in luteolin/SBE-β-CD inclusion complex.