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    嘌呤苯酰胺类化合物PLB-E和PLB-P在大鼠体内的药动学研究

    Pharmacokinetics of Purine Benzamides PLB-E and PLB-P in Rats

      摘要
    • 摘要:
      目的  建立HPLC分析方法测定大鼠血浆中抗肿瘤先导物嘌呤苯酰胺类化合物PLB-E、PLB-P的浓度并进行药动学研究。
      方法 采用所建立的HPLC测定分别静脉给药5、10、20 mg·kg–1(低、中、高3个剂量)的PLB-E、PLB-P后不同时间点的大鼠血浆药物浓度，利用DAS 3.3.0软件计算各化合物药动学参数。
      结果 PLB-E和PLB-P分别在2~120、3~60 μg·mL–1内线性关系良好(r2>0.999)；日内和日间精密度RSD均<15%；提取回收率分别为87.48%~92.84%，88.24%~92.60%。化合物PLB-E和PLB-P分别单次静脉注射5、10、20 mg·kg–1 3个剂量后的平均Cmax分别为(20.30±2.39)、(40.63±3.40)、(63.62±7.55)mg·L–1和(13.21±1.40)、(24.87±1.33)、(32.83±0.65)mg·L–1；AUC(0-∞)分别为(104.67±48.39)、(177.42±84.11)、(194.32±91.48)mg·h·L–1和(106.75±54.21)、(179.90±93.59)、(253.56±126.17) mg·h·L–1；各剂量给药Tmax均为0.08 h。
      结论 建立的HPLC经方法学验证符合生物样品测定要求，适用于PLB-E和PLB-P在大鼠血浆浓度测定及药动学研究。PLB-E和PLB-P在大鼠体内药动学过程符合二室模型，符合非线性动力学消除。

       

      Abstract:
      OBJECTIVE To establish a method for the determination of the concentrations of anti-tumor lead compounds purine benzamides PLB-E and PLB-P in rat plasma by HPLC and apply to study pharmacokinetics.
      METHODS The established HPLC was used to determine the plasma drug concentrations of rats at different time points after intravenous administration of 5, 10, 20 mg·kg–1 (low, medium, high doses) of PLB-E and PLB-P, and the pharmacokinetic parameters of each compound were calculated using DAS 3.3.0 software.
      RESULTS PLB-E and PLB-P had good linear relationship in the range of 2–120, 3–60 μg·mL–1, respectively(r2>0.999). The RSD of inter-day and intra-day precision were <15%. The extraction recoveries were 87.48%–92.84% and 88.24%–92.60%, respectively. The main pharmacokinetic parameters of PLB-E and PLB-P after a single intravenous injection of 5, 10, 20 mg·kg–1 were as follows, the average Cmax was (20.30±2.39), (40.63±3.40), (63.62±7.55)mg·L–1 and (13.21±1.40), (24.87±1.33), (32.83±0.65)mg·L–1, respectively. AUC(0-∞) were (104.67±48.39), (177.42±84.11), (194.32±91.48)mg·h·L–1 and (106.75±54.21), (179.90±93.59), (253.56±126.17)mg·h·L–1, respectively. Tmax of each dose was 0.08 h.
      CONCLUSION The HPLC method established in this study meets the requirements for the determination of biological samples through methodological verification, which is applicable to the determination of the concentration of PLB-E and PLB-P in rat plasma and the pharmacokinetic study. The pharmacokinetic process of PLB-E and PLB-P in rats conforms to the two-compartment model, and conforms to the nonlinear kinetic elimination.

       

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