克班宁贴剂在大鼠体内的药动学与药效学评价

Pharmacokinetic and Pharmacodynamic Evaluation of Crebanine Patch in Rats

    摘要
  • 摘要:
      目的  比较克班宁经皮和灌胃2种给药途径在大鼠体内的药动学差异性，评价克班宁贴剂经皮给药抗大鼠心律失常的效果, 以及克班宁对钙离子通道的作用机制。
      方法  采用HPLC法测定大鼠血浆中克班宁的浓度; 采用氯化钡(BaCl2)致大鼠心律失常的模型观察克班宁经皮给药的抗心律失常效果, 采用Whole Cell记录检测克班宁对钙通道电流的影响。
      结果  克班宁贴剂经皮给药(400 mg·kg-1)的主要药动学参数为: AUC0-∞=(204.500±170.496)mg·h·L-1; Tmax=(10.333±0.745)h; Cmax=(1.968±0.147)mg·L-1(n=6)。克班宁溶液灌胃给药(40 mg·kg-1)的主要药动学参数为: AUC0-∞=(26.980±6.672)mg·h·L-1; Tmax=(0.086±0.024)h; Cmax=(8.991±2.343)mg·L-1(n=6)。与阴性组比较, 79、158、316 mg·kg-1三个剂量克班宁贴剂组大鼠经皮给药后, 恢复窦性心律所需的时间均显著缩短(P < 0.01), 恢复窦性心律的鼠数均明显增多(P < 0.01);给药后≤20 min能够恢复窦性心律的鼠数均明显增多(P < 0.001);恢复窦性心律后维持时间>20 min的鼠数显著增多(P < 0.01)。克班宁对T型钙通道和L型钙通道均有较明显的抑制作用。
      结论  克班宁贴剂给药在大鼠体内消除慢, 具有缓释作用, 可通过抑制钙离子通道发挥对BaCl2致大鼠心律失常的明显抑制作用, 显著延长作用时间, 达到减毒增效的目的。

     

    Abstract:
      OBJECTIVE  To compare the pharmacokinetic differences between the percutaneous and intragastric administration of Crebanine in rats. To evaluate the effect of Crebanine patch on anti-arrhythmia in rats and the mechanism of Crebanine on calcium channel.
      METHODS  The plasma concentration of Crebanine in rats was determined by HPLC. The anti-arrhythmic effect of Crebanine transdermal administration was observed in the model of barium chloride induced arrhythmia in rats, and Whole Cell recording was used to detect the effect of Crebanine on calcium channel current.
      RESULTS  The main pharmacokinetic parameters of Crebanine patch for transdermal administration (400 mg·kg-1) were as follows: AUC0-∞=(204.500±170.496)mg·h·L-1; Tmax=(10.333±0.745)h; Cmax=(1.968±0.147)mg·L-1 (n=6). The main pharmacokinetic parameters of Crebanine solution for intragastric administration (40 mg·kg-1) were as follows: AUC0-∞=(26.980±6.672)mg·h·L-1; Tmax=(0.086±0.024)h; Cmax=(8.991±2.343)mg·L-1 (n=6). Compared with the negative group, the time required for recovery of sinus rhythm was significantly shortened (P < 0.01), and the number of rats recovering sinus rhythm significantly increased (P < 0.01) after transdermal administration of the patches in 79, 158, 316 mg·kg-1 groups. The number of rats that could recover sinus rhythm within 20 min after administration increased significantly (P < 0.001). The number of rats that maintained sinus rhythm for more than 20 min after the restoration increased significantly (P < 0.01). Both T-type and L-type calcium channels were inhibited by Crebanine.
      CONCLUSION  The administration of Crebanine patch has slow elimination and sustained release effect, can significantly inhibit barium chloride induced arrhythmia in rats by inhibiting calcium channels, and significantly prolong the action time, so as to achieve the purpose of reducing toxicity and increasing efficiency.

     

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