X射线辐射对埃克替尼大鼠体内药动学的影响  

Effect of X-ray on the pharmacokinetics of icotinib in vivo

作　　者：王玲梅 杨凡 梁博涵 张爱杰 王伟占 刘鉴峰[1,2] 董世奇 樊慧蓉 WANG Ling-mei;YANG Fan;LIANG Bo-han;ZHANG Ai-jie;WANG Wei-zhan;LIU Jian-feng;DONG Shi-qi;FAN Hui-rong(Institute of Radiation Medicine,Chinese Academy of Medical Sciences&Peking Union Medical College,Tianjin 300192,China;Key Laboratory of Radio-pharmacokinetics of Innovative Drug,Chinese Academy of Medical Sciences,Tianjin 300192,China;Department of Cardiology,Tianjin Fourth Central Hospital,Tianjin 300142,China)

机构地区：[1]中国医学科学院放射医学研究所,天津300192 [2]中国医学科学院创新药物放射性药代研究重点实验室,天津300192 [3]天津市第四中心医院心内科,天津300142

出　　处：《中国新药杂志》2024年第12期1262-1269,共8页Chinese Journal of New Drugs

基　　金：国家自然科学基金资助项目(82204509,82104284);中国医学科学院医学与健康科技创新工程项目(2022-I2M-2-002,2021-I2M-1-058)。

摘　　要：目的:建立测定大鼠血浆中埃克替尼浓度的LC-MS/MS定量分析方法,研究X射线辐照对埃克替尼在大鼠体内药动学的影响并探究其RT-PK(radiotherapy-pharmacokinetics)现象。方法:将SD大鼠随机分为对照组和辐射组,辐射组分别进行不同剂量、不同次数及不同部位的X射线照射,恢复24 h后和对照组同时灌胃给予15 mg·kg^(-1)埃克替尼,采集不同时间点大鼠血浆。用LC-MS/MS定量分析方法测定大鼠血浆样品中埃克替尼的浓度,计算药动学参数。结果:测定大鼠血浆中埃克替尼浓度的LC-MS/MS方法通过了严格的方法学验证。大鼠灌胃给予埃克替尼后,其药动学实验结果显示,单次照射后随辐射剂量增加,胸腔辐射组血药浓度-时间曲线下面积(AUC)呈增加趋势,但无统计学差异;连续5 d胸腔照射(RT_(2Gy))后埃克替尼AUC显著下降;单次腹腔照射(RT_(5Gy))后埃克替尼的达峰浓度(C_(max))显著下降,其他药动学参数无显著改变。结论:通过验证的LC-MS/MS方法快速、准确、灵敏,可应用于测定大鼠血浆埃克替尼的浓度。药动学吸收实验结果提示单次X射线辐射对埃克替尼药动学影响不显著,多次胸腔照射可能导致该药物血浆暴露量降低,提示临床应根据实际情况合理调整埃克替尼的用量。Objective:To establish a quantitative LC-MS/MS method for determination of icotinib concentration in rat plasma to investigate the effect of thoracic X-ray irradiation on the pharmacokinetics of icotinib in rats and investigate whether there is radiotherapy-pharmacokinetics(RT-PK)phenomenon for icotinib.Methods:SD rats were randomly divided into control and radiation groups.The radiation groups were irradiated with different dosages of X-ray for different times or at different sites.After 24 hours of recovery,15 mg·kg^(-1)of icotinib was given to rats by gavage and plasma was collected at different time points.The concentrations of icotinib in the plasma samples were determined by LC-MS/MS,and the pharmacokinetic parameters were calculated.Results:The LC-MS/MS method for determination of icotinib in rat plasma was validated successfully.The results of the pharmacokinetic experiments of icotinib showed that the aera under the curve(AUC)of icotinib of the thoracic radiation group increased with increasing dose of radiation after single irradiation,but there was no statistical difference.The icotinib AUC decreased significantly in the thoracic radiation group(RT_(2Gy))after radiation for five consecutive days.The C_(max)of icotinib decreased significantly in the abdominal irradiation group(RT_(5Gy)),but the other PK parameters did not change significantly.Conclusion:The validated LC-MS/MS method is rapid,accurate,and sensitive and can be applied to determine the concentration of icotinib in rat plasma.The results of pharmacokinetic experiments suggest that the effect of single X-ray radiation on the PK of icotinib is not significant,but multiple thoracic radiation may lead to a decrease in plasma exposure.The dosage of icotinib should be rationally adjusted in clinical therapy.

关 键 词：埃克替尼 辐射 药动学 液相色谱-质谱联用 

分 类 号：R969.1[医药卫生—药理学]