人血浆中尼洛替尼的LC-MS/MS测定法及其药动学应用  

Determination of nilotinib in human plasma by LC⁃MS/MS and its pharmacokinetic study

作　　者：马欢 周臻[1] 李周[1] 葛庆华[1] 康修远 MA Huan;ZHOU Zhen;LI Zhou;GE Qing-hua;KANG Xiu-yuan(National Advanced Medical Engineering Research Center,Shanghai 201203,China)

机构地区：[1]医药先进制造国家工程研究中心,上海201203

出　　处：《中国新药杂志》2024年第1期62-67,共6页Chinese Journal of New Drugs

摘　　要：目的:建立LC-MS/MS法测定人血浆中的尼洛替尼浓度,并应用于尼洛替尼胶囊中国健康受试者空腹药动学研究。方法:以氘代尼洛替尼为内标,血浆样品采用甲醇沉淀的方式分离蛋白并离心取上清液进样。色谱柱为Kinetex C_(18)柱(100 mm×2.1 mm,2.6μm)。流动相A为水(含0.1%甲酸和5 mmol·L^(-1)甲酸铵),流动相B为甲醇,67%B进样,流速为0.4 mL·min^(-1)。尼洛替尼及内标的离子对分别为530.25→289.30和536.25→295.30。方法经完整验证后,应用于12例中国健康受试者空腹药动学研究。结果:血浆中尼洛替尼在2~600 ng·mL^(-1)范围内线性关系良好,方法回收率为97.0%~104.3%,批内RSD≤4.18%,批间RSD≤6.43%。正常血浆无明显基质效应,分别在正常血浆中添加5%全血和2%脂肪乳剂考察特殊基质效应,证明溶血和高脂基质不影响测定准确性。12例中国健康受试者口服尼洛替尼胶囊后,经统计t_(1/2)为(24.7±32.2)h,C_(max)为(400.1±164.6)ng·mL^(-1),T_(max)为(2.4±0.9)h,AUC_(0→72)为(7900±2598)ng·mL^(-1)·h,AUC_(0→∞)为(9226±3649)ng·mL^(-1)·h。结论:本方法快速灵敏、准确度高、准确性好,适用于尼洛替尼的血药浓度测定及药动学研究。Objective:An LC⁃MS/MS method was established for the determination of nilotinib in human plasma,which was further applied to the pharmacokinetic study of nilotinib capsules in Chinese healthy subjects under fasting state.Methods:Deuterated nilotinib was used as the internal standard,and plasma samples were precipitated by methanol to separate proteins and centrifuged for supernatant injection.A Kinetex C18 column(100 mm×2.1 mm,2.6μm)was applied using mobile phase A of water(containing 0.1%formic acid and 5 mmol·L^(-1) ammonium formate)and B of methanol with 67%B was injected at a flow rate of 0.4 mL·min^(-1).The ion pairs are 530.25→289.30 and 536.25→295.30 for nilotinib and internal standard,respectively.After full validation,the method was applied to a pharmacokinetic study in 12 fasted Chinese healthy subjects.Results:Good linearity was achieved for nilotinib in the concentration range of 2~600 ng·mL^(-1).The recoveries were within 97.0%~104.3%,and intra⁃and inter⁃day RSDs were below 4.18%and 6.43%,respectively.No significant matrix effects were observed in normal blank plasma.The hemolyzed and hyperlipidemic plasma sample were made by adding 5%whole blood and 2%intralipid into normal blank plasma,respectively.The results indicated that hemolyzed and hyperlipidemic matrix did not affect the accuracy of the assay.After oral administration of nilotinib capsules in 12 fasted Chinese healthy subjects,t_(1/2) was(24.7±32.2)h,C_(max) was(400.1±164.6)ng·mL^(-1),T_(max) was(2.4±0.9)h,AUC_(0→72) was(7900±2598)ng·mL^(-1)·h,AUC_(0→∞) was(9226±3649)ng·mL^(-1)·h.Conclusion:This method is rapid and sensitive,highly accurate,and suitable for the determination of plasma concentrations of nilotinib and further pharmacokinetic studies.

关 键 词：尼洛替尼 LC-MS/MS法 方法验证 药动学 

分 类 号：R917[医药卫生—药物分析学]