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

关键词:  PLB-E  PLB-P  HPLC  血药浓度  药代动力学

Key words:  PLB-E  PLB-P  HPLC  plasma concentration  pharmacokinetics

摘要:

目的 建立HPLC分析方法测定大鼠血浆中抗肿瘤先导物PLB-E、PLB-P的浓度并进行药动学研究。 方法 采用所建立HPLC法测定分别静脉给药5、10、20 mg·kg-1(低、中、高三个剂量)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 μg·mL-1，3~60 μg·mL-1内线性关系良好(r2>0.999)；日内和日间精密度RSD均小于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-1三个剂量后的主要药动学参数：平均Cmax分别为20.301±2.393、40.633±3.402、63.616±7.547 mg·L-1和13.213±1.395、24.866±1.328、32.829±0.649 mg·L-1；AUC(0-∞)分别为104.670±48.391、177.419±84.109、194.317±91.477 mg·h·L-1和106.753±54.206、179.898±93.593、253.563±126.168 mg·h·L-1；各剂量给药Tmax均为0.08 h。 结论 本研究所建立的HPLC法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在大鼠体内药代动力学过程符合二室模型，符合非线性动力学消除。本实验结果可为后续的药效学、毒理学研究奠定实验基础，继而进一步为该先导物研发评估及其临床研究提供重要参考。

Abstract:

OBJECTIVE To establish a method for the determination of the concentrations of anti-tumor lead compounds PLB-E and PLB-P in rat plasma by HPLC and apply to study pharmacokinetics. METHODS The established HPLC method 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 have good linear relationship in the range of 2~120 μg·mL-1 and 3~60 μg·mL-1 respectively (r2>0.999); The RSD of inter-day and intra-day precision are less than 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 20.301±2.393, 40.633±3.402, 63.616±7.547 mg·L-1 and 13.213±1.395, 24.866±1.328, 32.829±0.649 mg·L-1, respectively; AUC(0-∞) were 104.670±48.391, 177.419±84.109, 194.317±91.477 mg·h·L-1 and 106.753±54.206, 179.898±93.593, 253.563±126.168 mg·h·L-1, respectively; Tmax of each dose is 0.08 h. CONCLUSION The HPLC method established in this study meets the requirements for the determination of biological samples through methodological verification, and 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. The results of this experiment can lay an experimental foundation for the follow-up pharmacodynamics and toxicology research, and then provide an important reference for the R&D evaluation and clinical research of the lead.