摘要
目的用超高压液相色谱串联四级杆飞行时间质谱技术(UPLC-Q-TOF-MS/MS)分析方法鉴定辐射组和正常组大鼠体内阿帕替尼的代谢产物,探究X射线辐射对阿帕替尼体内代谢的影响。方法将大鼠随机分成4组,辐射1组、辐射2组大鼠进行X射线腹腔照射,照射剂量为2 Gy,正常1组和正常2组大鼠不照射,照射完成后24 h,4组大鼠均灌胃给予45 mg·kg^(-1)阿帕替尼。采集大鼠给药前和给药后的血浆、尿样和粪样。生物样品经固相萃取法处理后进行UPLC-Q-TOF-MS/MS分析,用Peakview和Metabolitepilot软件鉴定阿帕替尼的代谢产物。结果在正常组大鼠体内检测到53个代谢产物,包括46个Ⅰ相代谢产物和7个Ⅱ相代谢产物。在辐射组大鼠体内发现64个代谢产物,包括54个Ⅰ相代谢产物和10个Ⅱ相代谢产物。在正常1组和辐射1组大鼠血浆中代谢产物无差异;与正常2组相比,辐射2组大鼠尿中增加了5个代谢产物,粪中增加了9个代谢产物。阿帕替尼在正常组大鼠体内的主要代谢途径包括氧化、N-脱烷基化、水解、脱氢化、氢化、硫酸酯化、葡萄糖醛酸化。与正常组相比,X射线辐射增加了部分脱氢化代谢产物,新增了甲氧基化代谢产物和S-半胱氨酸结合代谢产物。结论X射线辐射影响了阿帕替尼在大鼠体内的代谢途径,增加了尿和粪中代谢产物种类,这可能是产生“放疗调节药代动力学”现象的直接原因。本研究为临床放化疗中阿帕替尼的剂量调整和合理用药提供研究基础。
Objective To study the metabolites of apatinib in the normal and radiation groups of rats identified by ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS/MS)analysis to investigate the effect of X-ray radiation on the metabolism of apatinib in vivo.Methods Rats were randomly divided into four groups,radiation group 1 and radiation group 2 were irradiated with intraperitoneal X-rays at a dose of 2 Gy,while normal group 1 and normal group 2 were not irradiated.After 24 h of recovery from radiation,all groups were given 45 mg·kg^(-1) apatinib by gavage.Plasma,urine and faeces samples were collected before and after the administration of the drug.The biological samples were processed by solid phase extraction and then analyzed by UPLC-Q-TOF-MS/MS.The metabolites of Apatinib were identified using Peakview and Metabolitepilot software.Results A total of 53 metabolites,including 46 phase Ⅰ metabolites and 7 phaseⅡmetabolites,were detected in the normal group of rats.A total of 64 metabolites,including 54 phase Ⅰ metabolites and 10 phaseⅡmetabolites,were detected in the radiation group rats.There was no difference in metabolites between normal group 1 and radiation group 1.Compared to the normal group 2,the radiation group 2 showed an increase of 5 metabolites in the urine and 9 metabolites in the feces.The major metabolic pathways of apatinib in the normal group of rats included hydroxylation,N-dealkylation,hydrolysis,dehydrogenation,hydrogenation,sulfate esterification,and glucuronidation.Compared with the normal group,X-ray radiation increased some of the dehydrogenated metabolites and added new methoxylated metabolites and S-cysteine binding metabolites.Conclusion The metabolic pathway of apatinib in rats was altered by X-ray radiation,which increased the metabolite species in urine and feces.The changes in the metabolism of apatinib in vivo may be the direct cause of the"radiotherapy-pharmacokinetic"phenomenon.This study provides a basis for the do
作者
董世奇
杨凡
王玲梅
刘鉴峰
张爱杰
樊慧蓉
DONG Shi-qi;YANG Fan;WANG Ling-mei;LIU Jian-feng;ZHANG Ai-jie;FAN Hui-rong(Key Laboratory of Radiopharmacokinet-ics for Innovative Drugs,Institute of Radiation Medicine,Chinese Academy of Medical Sciences&Peking Union Medical College,Tianjin 300192,China)
出处
《中国临床药理学杂志》
CAS
CSCD
北大核心
2023年第11期1592-1597,共6页
The Chinese Journal of Clinical Pharmacology
基金
中央高校基本科研业务费专项基金资助项目(3332021064)
国家自然科学基金资助项目(82104284)
天津市杰出青年科学基金资助项目(18JCJQJC47300)
中国医学科学院中央级公益性科研院所基本科研业务费专项基金资助项目(2018PT35031)
中国医学科学院医学与健康科技创新工程基金资助项目(2022-I2M-2-002)。
关键词
阿帕替尼
X射线辐射
超高压液相色谱串联四级杆飞行时间质谱技术
代谢
apatinib
X-ray radiation
ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry
metabolism
