超滤法结合液质联用技术测定抗肿瘤化合物CJ-6在不同种属中的血浆蛋白结合率  

Ultrafiltration combined with LC-MS/MS technology to determine the plasma protein binding rate of anti-tumor compound CJ-6 in different species

作　　者：张宇 廖伟科 刘举[2] 李爱红 程虎 汤磊 ZHANG Yu;LIAO Wei-ke;LIU Ju;LI Ai-hong;CHENG Hu;TANG Lei(School of Pharmacy,Guizhou Medical University,Guizhou Guiyang 550004,China;School of Pharmacy,Liaoning University,Liaoning Shenyang 110136,China;Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D,Guizhou Guiyang 550004,China)

机构地区：[1]贵州医科大学药学院,贵州贵阳550004 [2]辽宁大学药学院,辽宁沈阳110136 [3]贵州省化学合成药物研发利用工程技术研究中心,贵州贵阳550004

出　　处：《中国医院药学杂志》2022年第2期114-118,共5页Chinese Journal of Hospital Pharmacy

基　　金：国家自然科学青年基金(编号:81903472);贵州省高层次创新型“百”层次人才项目(编号:黔科合人才(2016)4015号)。

摘　　要：目的:通过建立测定血浆中抗肿瘤化合物N-(4-((2-(环丙烷甲酰胺)吡啶-4-基)氧基)-3-氟苯基)-4-甲基-3,5-二氧基-2-苯基-2,3,4,5-四氢-1,2,4-三嗪-6-甲酰胺(CJ-6)的分析方法,测定CJ-6在不同种属(大鼠、猴、人)中的血浆蛋白结合率。方法:采取超滤法测定CJ-6在大鼠、猴、人血浆中的血浆蛋白结合率,以超滤法结合液质联用技术(LC-MS/MS)检测孵育液及超滤液中CJ-6的含量,计算CJ-6的血浆蛋白结合率。结果:CJ-6在低、中、高浓度(0.1,1,10μmol·L^(-1))下的大鼠血浆中的血浆蛋白结合率分别为(89.61±2.07)%,(92.94±1.15)%,(97.64±1.59)%;在猴血浆中的血浆蛋白结合率分别为(98.11±2.21)%,(98.46±1.58)%,(98.87±1.40)%;在人血浆中的血浆蛋白结合率分别为(98.42±2.54)%,(98.81±1.73)%,(99.30±1.26)%。其中,在低、中浓度(0.1,1μmol·L^(-1))下,CJ-6在大鼠血浆中的血浆蛋白结合率明显低于猴及人血浆中的血浆蛋白结合率;在高浓度(10μmol·L^(-1))下,在3个种属血浆中的血浆蛋白结合率没有明显的差异。结论:建立的LC-MS/MS法简便、稳定、可靠,可用于CJ-6的含量测定,CJ-6在人、猴种属中血浆蛋白结合率与药物浓度无明显浓度依赖性,仅在大鼠血浆中,表现出一定的浓度依赖性。OBJECTIVE An analytical method for the determination of N-(4-((2-(cyclopropane formamide)pyridin-4-yl)oxy)-3-fluorophenyl)-4-methyl-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-formamide(CJ-6)in plasma was established to determine the plasma protein binding rate of CJ-6 in different species(rats,monkeys and humans)METHODS The ultrafiltration method was used to determine the plasma protein binding rate of CJ-6 in the plasma of rats,monkeys,and humans,The content of CJ-6 in incubation solution and ultrafiltration filtrate was detected by ultrafiltration combined with liquid mass spectrometry(LC-MS/MS).RESULTS The plasma protein binding rate of J-6 in rat plasma at low,medium,and high(0.1,1,10μmol·L^(-1))concentrations were(89.61±2.07)%,(92.94±1.15)%,(97.64±1.59)%,respectively;the plasma protein binding rate in monkey plasma is(98.11±2.21)%,(98.46±1.58)%,(98.87±1.40)%,respectively;The plasma protein binding rate in human plasma is(98.42±2.54)%,(98.81±1.73)%,(99.30±1.26)%,respectively.Among them,at low and medium concentrations(0.1,1μmol·L^(-1)),the plasma protein binding rate of CJ-6 in rat plasma was significantly lower than that in monkey and human plasma;At a high concentration(10μmol·L^(-1)),there was no significant difference in the plasma protein binding rate in the plasma of the three species.CONCLUSION The established LC-MS/MS method is simple,stable and reliable,and can be used for the determination of CJ-6,the plasma protein binding rate and drug concentration are not significant in human and monkey species Concentration dependence,only in rat plasma,showing a certain concentration dependence.

关 键 词：抗肿瘤化合物CJ-6 超滤法 LC-MS法 血浆蛋白结合率 

分 类 号：R96[医药卫生—药理学]