基于膝骨性关节炎大鼠模型弩药微乳多成分PK-PD结合模型的建立

Establishment of PK-PD Binding Model for Multi-Components of Crossbow Medicine Microemulsion Based on a Rat Model of Knee Osteoarthritis

    摘要
  • 摘要:
    目的 建立弩药微乳多成分(苯甲酰新乌头原碱、苯甲酰次乌头原碱、新乌头碱、杠柳毒苷、新绿原酸、香草酸、绿原酸)膝骨性关节炎(KOA)的药动学(PK)-药效学(PD)结合模型，阐明弩药微乳在KOA大鼠体内的动态变化及与药效消长之间的相互关系。
    方法 利用4%木瓜蛋白酶诱导建立KOA大鼠模型；经UPLC分析弩药微乳多成分在大鼠关节液中的PK过程，建立PK模型；经ELISA分析测定给药后不同时间点KOA大鼠MMP-3、MMP-13、TNF-α及IL-1β含量，建立PD模型；应用Phoenix WinNonlin软件拟合PK与PD数据得到PK-PD模型。
    结果 PK结果显示弩药微乳多成分在关节腔内吸收缓慢，在3~5 h内逐步达到峰值，其中苯甲酰新乌头原碱、苯甲酰次乌头原碱、新乌头碱、杠柳毒苷、新绿原酸、香草酸及绿原酸的Cmax分别为1.23、1.48、1.62、4.67、0.93、1.25、2.35 μg·mL-1；药-时曲线下面积(AUC0-11)分别为2.58、4.04、3.54、12.15、2.51、2.41、4.11 h·μg·mL-1。PD结果显示给药不同时间点后，MMP-3、IL-1β、TNF-α、MMP-13含量均有不同程度的下降，其中MMP-3下降不明显，仅在6 h有显著性差异；其余IL-1β、TNF-α、MMP-13含量均下降明显(P＜0.05，P＜0.01)，并出现药效滞后现象；PK-PD结合模型显示，弩药微乳多成分药物浓度与其药效数据能较好地拟合。
    结论 建立的PK-PD结合模型可对给药后的药效变化进行预估，为弩药微乳治疗KOA提供了相应的参考。

     

    Abstract:
    OBJECTIVE To establish a combined pharmacokinetic (PK)-pharmacodynamic (PD) model for knee osteoarthritis (KOA) of crossbow drug microemulsion multi-components (benzoylmesaconine, benzoylhypacoitine, mesaconitine, periplocin, neochlorogenic acid, vanillic acid, chlorogenic acid), and elucidate the dynamic changes in the KOA rats and the interrelation with the elapsed efficacy of the drug.
    METHODS A KOA rat model was induced by 4% papain; the PK process of crossbow medicine microemulsion components in rat synovial fluid was analyzed by UPLC to establish a PK model; the contents of MMP-3, MMP-13, TNF-α and IL-1β in KOA rats at different time points after administration were determined by ELISA analysis to establish a PD model; Phoenix WinNonlin software was used to fit the PK and PD data to obtain a PK-PD model.
    RESULTS PK results showed that the multi-components of the microemulsion were slowly absorbed in the joint cavity and gradually reached the peak value within 3-5 h. The Cmax of benzoylmesaconine, benzoylhypacoitine mesaconitine, periplocoside, neochlorogenic acid, vanillic acid and chlorogenic acid were 1.23, 1.48, 1.62, 4.67, 0.93, 1.25 and 2.35 μg·mL-1, respectively; the area under the drug-time curve (AUC0-11) was 2.58, 4.04, 3.54, 12.15, 2.51, 2.41 and 4.11 h·μg·mL-1, respectively. PD results showed that at different time points after administration, the contents of MMP-3, IL-1β, TNF-α, and MMP-13 decreased to varying degrees, among which MMP-3 decreased insignificantly, with significant differences only at 6 h; the contents of the remaining IL-1β, TNF-α, and MMP-13 decreased significantly (P < 0.05, P < 0.01), and showed the phenomenon of lagged efficacy; the PK-PD binding model showed that the drug concentration of the multi-component drug in the crossbow medicine microemulsion could be well fitted with its drug efficacy data.
    CONCLUSION The established PK-PD binding model can predict the drug efficacy changes after administration, and provides a corresponding reference for the crossbow medicine microemulsion treatment of KOA.

     

    • HTML全文
    • 参考文献(16)
    • 相关文章
    • 施引文献
  • 资源附件(0)

/

返回文章
返回