SPG复方主要成分配伍给药在大鼠体内药动学参数研究

Research on Pharmacokinetic Parameters of Active Ingredients in SPG Formula by Oral Administration in Rats

目的：研究SPG复方主要成分丹酚酸B、芍药苷和甘草酸不同剂量复配给药在大鼠体内的药动学参数特征,并探讨配伍剂量对各参数的影响。方法：灌胃给予大鼠3种活性成分低、中、高3个剂量复配混合液,经眼眶静脉丛取血,血浆样品采用液-液萃取法处理,并以氯霉素为内标、以HPLC-MS/MRM测定血浆中3种成分浓度。血药浓度数据用Win Nonlin 7.0软件按非房室模型处理,计算药动学参数,并采用SPSS 18.0统计软件进行分析。结果：丹酚酸B、芍药苷、甘草酸3个浓度的血药浓度-时间曲线均呈现一级动力学特征（相关系数分别为0.999、0.983和0.982）。与低剂量组相比,复配给药丹酚酸B中、高剂量组的体内驻留时间（MRT）、表观分布容积（Vd）、清除率（CL）均呈现显著下降趋势（P〈0.01）;与低剂量组相比,复配给药芍药苷中、高剂量组的半衰期（t1/2）、Vd均呈现显著下降趋势（P〈0.01）;中、高剂量组甘草酸的药时曲线出现二次吸收峰,复配给药剂量对甘草酸各药动学参数未呈现规律性影响。结论：复配给药各成分剂量与血药浓度呈现非线性动力学特征。丹酚酸B口服吸收可能存在高浓度饱和抑制;随着配伍剂量增加,芍药苷消除加快;复配给药剂量增加对甘草酸的二次吸收影响显著。

Objective：Salvianolic acid B（Sal B）,paeoniflorin（PF）and glycyrrhizin（GL）are bioactive components in SPG formula. This study investigated the pharmacokinetic parameters of three compounds after oral administration of different dose of combinations,and explored the effect of compatibility dose on parameters. Methods：The rats were given the mixed compounds of low,medium and high doses by oral administration,and the blood samples were purified by liquid-liquid extraction with formic acid and acetonitrile. With chloramphenicol as internal standard,the concentrations of three compounds in plasma were determined by high-performance liquid chromatography-tandem mass spectrometry with multiplereaction monitoring（HPLC-MS/MRM）. The pharmacokinetic parameters of the three compounds were calculated with Win Nonlin 7.0 software using non-compartmental methods and analyzed by SPSS 18.0 statistical software. Results：Plasma concentration-time curve of Sal B,PF and GL showed first-order kinetic characteristics,respectively（r=0.999,0.983,0.982）. In comparison with the group of low dose,the pharmacokinetic parameters（CL,Vd,MRT）of Sal B in the medium and high group were decreased（P〈0.01）. The parameters of PF（t1/2,Vd）in medium and high group declined significantly（P〈0.01）compared with low group. About GL,there was two absorption peaks among the plasma concentration time curves in medium and high group,and there were no statistically significant differences in pharmacokinetic parameters in different doses. Conclusion：Nonlinear dynamics are presented between the dose of mixed compounds and their plasma concentration. High protein binding rate of Sal B might result in relatively low oral bioavailability with saturation suppressed of increasing dose. The doses of three mixed compounds have a significant impact on the elimination of PF and secondary absorption of GL.