葡聚糖木炭吸附法测定多肽类候选药物的血浆蛋白结合率  

Determination of plasma protein binding of peptide drug candidates by dex⁃tran-coated charcoal

作　　者：张莉 江程[1,2] 陈思敏 姚婷 向宁铃 苏梦翔 狄斌[1,2] ZHANG Li;JIANG Cheng;CHEN Simin;YAO Ting;Xiang Ningling;SU Mengxiang;DI Bin(School of Pharmacy,China Pharmaceutical University,Nanjing 210009;Jiangsu Key Laboratory of Drug Molecular Design and Drug Optimization,Nanjing 210009,China)

机构地区：[1]中国药科大学药学院,南京210009 [2]江苏省药物分子设计与成药性优化重点实验室,南京210009

出　　处：《中国药科大学学报》2020年第5期522-529,共8页Journal of China Pharmaceutical University

基　　金：国家自然科学基金资助项目(No.81872833,No.81773693)。

摘　　要：由于某些多肽类药物在半透膜上具有非特异性吸附或者在血浆中的稳定性较差,在测定其蛋白结合率时不能适用于经典的平衡透析法和超滤法。运用葡聚糖木炭吸附法结合液质联用技术,基于候选药物吸附至葡聚糖木炭的初始速率动力学原理,选择7条具有相同氨基酸序列、不同构型的磷酸化六肽为研究模型肽,测定了其在大鼠血浆中的蛋白结合率,总结了影响多肽候选药物蛋白结合率变化的氨基酸位点规律。研究结果表明,葡聚糖木炭吸附法作为一种血浆蛋白结合率测定的补充方法,适用于传统实验技术无法测定的多肽或者有机候选药物。The conventional equilibrium dialysis and ultrafiltration methods cannot be used to determine the protein binding of some peptides because of their non-specific adsorption on the semipermeable membrane or poor stability in the plasma.The method of dextran-coated charcoal adsorption combined with LC-MS/MS were used.Based on the kinetic principle of initial rate of candidate drugs absorbed to dextran-coated charcoal,seven phosphorylated peptides with the same amino acid sequence and different configurations in rat plasma were selected as the study model using;the protein binding in rat plasma were determined;the amino acid distribution rules affecting the changes in protein binding rates of peptide candidate drugs were summarized.The results suggest that the dextran charcoal adsorption method,as a supplementary method for the determination of plasma protein binding,is suitable for peptides or organic drug candidates that cannot be determined by traditional techniques.

关 键 词：多肽药物 血浆蛋白结合率 葡聚糖木炭吸附法 成药性评价 液相色谱-质谱联用 

分 类 号：R917[医药卫生—药物分析学]