抗肿瘤新化合物LS-177在不同种属中血浆蛋白结合率的测定
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摘要
目的:建立血浆中LS-177的分析方法,测定LS-177与大鼠、比格犬和人的血浆蛋白结合率。方法:采用平衡透析法模拟LS-177在体内与血浆蛋白的结合过程,采用UPLC-MS/MS方法对透析外液和内液中LS-177的含量进行测定,计算LS-177与大鼠、比格犬和人的血浆蛋白结合率。结果:LS-177低、中、高(25,50和100 ng·m L-1) 3个浓度的大鼠血浆蛋白结合率分别是(81. 2±5. 2)%,(77. 2±6. 2)%,(79. 8±5. 2)%;比格犬血浆蛋白结合率分别是(84. 2±2. 7)%,(82. 5±3. 1)%,(84. 1±3. 9)%;人血浆蛋白结合率分别是(84. 0±3. 4)%,(81. 7±4. 0)%,(80. 5±3. 4)%。结论:建立的LS-177蛋白结合率测定方法简便、稳定、可靠,LS-177血浆蛋白结合率不具有明显的浓度依赖性和种属差异。
Objective: To establisha method for the analysis of LS-177 in plasma and determination the plasma protein binding rate of LS-177 and different species plasma protein( Rat,Beagle and human). Methods:Equilibrium dialysis method was utilized to imitate the binding process between LS-177 and different species plasma protein. The concentration of LS-177 in and out of the dialysis membrane was determined by UPLC-MS/MS and the plasma protein binding rates of LS-177 and different species plasma protein( Rat,Beagle and human) were calculated.Results: Plasma protein binding rates of LS-177 at three various concentrations( 25,50 and 100 ng·m L-1) were( 81. 2 ±5. 2) %,( 77. 2 ±6. 2) %,( 79. 8 ± 5. 2) % in rat plasma;( 84. 2 ± 2. 7) %,( 82. 5 ± 3. 1) %,( 84. 1 ±3. 9) % in beagle plasma and( 84. 0 ± 3. 4) %,( 81. 7 ± 4. 0) %,( 80. 5 ± 3. 4) % in human plasma,respectively.Conclusion: This method for determining plasma protein binding rates of LS-177 was simple,stable and reliable.The plasma protein binding rate of LS-177 has no significance concentration dependent and species differences.
Objective: To establisha method for the analysis of LS-177 in plasma and determination the plasma protein binding rate of LS-177 and different species plasma protein( Rat,Beagle and human). Methods:Equilibrium dialysis method was utilized to imitate the binding process between LS-177 and different species plasma protein. The concentration of LS-177 in and out of the dialysis membrane was determined by UPLC-MS/MS and the plasma protein binding rates of LS-177 and different species plasma protein( Rat,Beagle and human) were calculated.Results: Plasma protein binding rates of LS-177 at three various concentrations( 25,50 and 100 ng·m L-1) were( 81. 2 ±5. 2) %,( 77. 2 ±6. 2) %,( 79. 8 ± 5. 2) % in rat plasma;( 84. 2 ± 2. 7) %,( 82. 5 ± 3. 1) %,( 84. 1 ±3. 9) % in beagle plasma and( 84. 0 ± 3. 4) %,( 81. 7 ± 4. 0) %,( 80. 5 ± 3. 4) % in human plasma,respectively.Conclusion: This method for determining plasma protein binding rates of LS-177 was simple,stable and reliable.The plasma protein binding rate of LS-177 has no significance concentration dependent and species differences.
引文
[1]茆勇军,李海泓,李剑锋,等.蛋白酪氨酸激酶信号转导途径与抗肿瘤药物[J].药学学报,2008,43(4):323-334.
[2]李欣,高金恒,陈国良.蛋白酪氨酸激酶抑制剂的研究进展[J].沈阳药科大学学报,2011,28(12):1005-1012.
[3]康从民,代英杰,王巧燕,等.小分子蛋白酪氨酸激酶抑制剂及其作用机制[J].中国新药杂志,2013,22(10):1170-1178.
[4]熊康萍,刘宏,沈晶晶.酪氨酸激酶类抗肿瘤作用靶点的研究进展[J].中国新药杂志,2015,24(4):403-408.
[5] QIAN CN,GUO X,CAO B,et al. Met protein expression level correlates with survival in patients with late-stage nasopharyngeal carcinoma[J]. Cancer Res,2002,62(2):589-596.
[6] DUSSAULT I,BRLLON SF. From concept to reality:the long road to c-Met and RON receptor tyrosine kinase inhibitors for the treatment of cancer[J]. Anticancer Agents Med Chem,2009,9(2):221-229.
[7] BURGESS T,COXON A,MEYER S,et al. Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors[J]. Cancer Res,2006,66(3):1721-1729.
[8] CHRISTENSEN JG,BURROWS J,SALGIA R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention[J]. Cancer Let,2005,225(1):1-26.
[9]孙燕来,李增军.肝细胞生长因子及其受体c-Met表达与胃癌肝转移的相关性[J].实用医学杂志,2015,31(16):2634-2637.
[10]乔洪源,陈建新,余宗阳,等. HGF及其c-MET受体在非小细胞肺癌中的研究进展[J].中国肿瘤,2014,23(2):141-147.
[11] XU YY,PENG Z,LI ZW,et al. Expression and clinical significance of c-Met in advanced esophageal squamous cell carcinoma[J]. BMC Cancer,2015,15(1):1-7.
[12] LI S,ZHAO Y,WANG K,et al. Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors[J].Bioorg Med Chem,2013,21(11):2843-2855.
[13] TANG Q,ZHAO Y,DU X,et al. Design,synthesis,and structure-activity relationships of novel 6, 7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents[J]. Eur J Med Chem,2013,69(69c):77-89.
[14] CHOUEIRI TK,VAISHAMPAYAN U,ROSENBERG JE,et al.Phase II and biomarker study of the dual MET/VEGFR2 inhibitorforetinib in patients with papillary renal cell carcinoma[J]. J Clin Oncol,2013,31(2):181-186.
[15]丁薇,赵云丽,汪小瑞,等.顶空气相色谱法测定LS-177中的8种有机溶剂残留量[J].沈阳药科大学学报,2014,31(8):618-621.
[16] JU P,LIU ZZ,JIANG Y,et al. Determination of a novel anticancer c-Met inhibitor LS-177 in rat plasma and tissues with a validated UPLC-MS/MS method:application to pharmacokinetics and tissue distribution study[J]. Biomed Chromatogr,2015,29(7):1103-1111.
[17] ZHANG LH,JU P,ZHOU FF,et al. The absolute bioavailability investigation of LS-177 in rats using ultra-performance liquid chromatography tandem mass spectrometry[J]. Drug Test Anal,2015,7(9):756-762.
[18] CDER(Center for Drug Evaluation and Research),Guidance for Industry,Bioanalytical Method Validation[S]. 2001.
[19] HUANG Y,CHEN H,HE F,etal. Simultaneous determination of humanplasma protein binding of bioactive flavonoids in Polygonum orientale by equilibrium dialysis combined with UPLC-MS/MS[J]. J Pharmaceut,2013,3(5):376-381.
[20]刘睿,谢跃生,潘桂湘,等.药物血浆蛋白结合率测定方法的研究进展[J].天津中医药,2007,12(24):526-528.
[2]李欣,高金恒,陈国良.蛋白酪氨酸激酶抑制剂的研究进展[J].沈阳药科大学学报,2011,28(12):1005-1012.
[3]康从民,代英杰,王巧燕,等.小分子蛋白酪氨酸激酶抑制剂及其作用机制[J].中国新药杂志,2013,22(10):1170-1178.
[4]熊康萍,刘宏,沈晶晶.酪氨酸激酶类抗肿瘤作用靶点的研究进展[J].中国新药杂志,2015,24(4):403-408.
[5] QIAN CN,GUO X,CAO B,et al. Met protein expression level correlates with survival in patients with late-stage nasopharyngeal carcinoma[J]. Cancer Res,2002,62(2):589-596.
[6] DUSSAULT I,BRLLON SF. From concept to reality:the long road to c-Met and RON receptor tyrosine kinase inhibitors for the treatment of cancer[J]. Anticancer Agents Med Chem,2009,9(2):221-229.
[7] BURGESS T,COXON A,MEYER S,et al. Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors[J]. Cancer Res,2006,66(3):1721-1729.
[8] CHRISTENSEN JG,BURROWS J,SALGIA R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention[J]. Cancer Let,2005,225(1):1-26.
[9]孙燕来,李增军.肝细胞生长因子及其受体c-Met表达与胃癌肝转移的相关性[J].实用医学杂志,2015,31(16):2634-2637.
[10]乔洪源,陈建新,余宗阳,等. HGF及其c-MET受体在非小细胞肺癌中的研究进展[J].中国肿瘤,2014,23(2):141-147.
[11] XU YY,PENG Z,LI ZW,et al. Expression and clinical significance of c-Met in advanced esophageal squamous cell carcinoma[J]. BMC Cancer,2015,15(1):1-7.
[12] LI S,ZHAO Y,WANG K,et al. Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors[J].Bioorg Med Chem,2013,21(11):2843-2855.
[13] TANG Q,ZHAO Y,DU X,et al. Design,synthesis,and structure-activity relationships of novel 6, 7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents[J]. Eur J Med Chem,2013,69(69c):77-89.
[14] CHOUEIRI TK,VAISHAMPAYAN U,ROSENBERG JE,et al.Phase II and biomarker study of the dual MET/VEGFR2 inhibitorforetinib in patients with papillary renal cell carcinoma[J]. J Clin Oncol,2013,31(2):181-186.
[15]丁薇,赵云丽,汪小瑞,等.顶空气相色谱法测定LS-177中的8种有机溶剂残留量[J].沈阳药科大学学报,2014,31(8):618-621.
[16] JU P,LIU ZZ,JIANG Y,et al. Determination of a novel anticancer c-Met inhibitor LS-177 in rat plasma and tissues with a validated UPLC-MS/MS method:application to pharmacokinetics and tissue distribution study[J]. Biomed Chromatogr,2015,29(7):1103-1111.
[17] ZHANG LH,JU P,ZHOU FF,et al. The absolute bioavailability investigation of LS-177 in rats using ultra-performance liquid chromatography tandem mass spectrometry[J]. Drug Test Anal,2015,7(9):756-762.
[18] CDER(Center for Drug Evaluation and Research),Guidance for Industry,Bioanalytical Method Validation[S]. 2001.
[19] HUANG Y,CHEN H,HE F,etal. Simultaneous determination of humanplasma protein binding of bioactive flavonoids in Polygonum orientale by equilibrium dialysis combined with UPLC-MS/MS[J]. J Pharmaceut,2013,3(5):376-381.
[20]刘睿,谢跃生,潘桂湘,等.药物血浆蛋白结合率测定方法的研究进展[J].天津中医药,2007,12(24):526-528.