目的 建立测定比格犬血浆中酒石酸长春瑞滨浓度的LC-MS/MS方法并用于毒代动力学研究。方法 选择12只比格犬分为3组，分别给予0.29、0.58、1.174 mg/kg注射用长春瑞滨胶束，分别于给药前及给药后0.03、0.25、0.5、1、2、4、8、12、24、48、72 h采集血样；用蛋白沉淀法处理血浆，采用API4000三重四极杆串联质谱仪测定浓度，离子化方式为电喷雾－正离子（ESI），监测方式为多反应监测，酒石酸长春瑞滨监测离子对m/z 779.3/122.4，兰索拉唑（IS）监测离子对m/z 392.0/188.1。色谱柱为inertsil ODS-3（50 mm×4.6 mm，5 μm），流动相为甲醇-5.0 mmol/L乙酸铵（含0.02%甲酸）梯度洗脱，体积流量为0.3 mL/min，柱温为35℃。结果 酒石酸长春瑞滨在1～1 000 ng/mL线性关系良好（r²=0.997 9）；定量限为1.0 ng/mL，回收率为104.38%～106.15%，基质效应为98.31%～107.37%，日间精密度为4.43%～8.92%，日内精密度为2.20%～8.40%。低、中、高剂量组AUC_{0~72 h}分别为（163.6±153.6）、（200.4±50.7）、（388.4±266.6）μg/L·h，峰浓度（C_max）分别为（142.9±127.0）、（198.4±107.8）、（442.5±259.9）μg/L。结论 本法简单、快速、灵敏度高、重复性好，可用于注射用酒石酸长春瑞滨胶束比格犬体内毒代动力学研究。比格犬静脉注射给予注射用酒石酸长春瑞滨胶束后，AUC_{0~72 h}及C_max与剂量均呈正相关。

Objective To establish a LC-MS/MS method for the determination of vinorelbine tartrate in Beagle dog plasma and to study its toxicokinetics. Methods 12 Beagle dogs were divided into three groups, who received single dose of 0.29, 0.58, and 1.174 mg/kg vinorelbine tartrate micelle for injection, respectively. Blood samples were collected at 0.03, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72 h before and after administration respectively. The plasma was treated with precipitation by methanol. The API4000 triple quadrupole electrospray tandem mass spectrometry was used to determine the concentration. The ionization mode was electrospray positive ion (ESI). The monitoring method was multi reaction monitoring. The vinorelbine tartrate monitoring ion pair was m/z 779.3/122.4, and lansoprazole (IS) monitoring ion pair was m/z 392.0/188.1. The analysis was performed on a Inertsil ODS-3 column (50 mm×4.6 mm, 5 μm), the mobile phase was methanol-5.0 mmol/L ammonium acetate (containing 0.02% formic acid) with gradient elution. The volume flow rate was 0.3 mL/min, and the column temperature was 35℃. Results The concentration range from 1 to 1 000 ng/mL had a good linearity (r²=0.997 9). The quantitative limit was 1.0 ng/mL, the recovery was 104.38%-106.15%, the matrix effect was 98.31%-107.37%, the day precision was 4.43%-8.92%, and the day precision was 2.20%-8.40%. The AUC_{0-72 h} in low, medium and high dose groups were (163.6 + 153.6), (200.4 + 50.7), (388.4 + 266.6) μg/L·h, and peak concentrations (C_max) were (142.9 + 127.0), (198.4 + 107.8), (442.5 + 259.9) μg/L, respectively. Conclusion The method is simple, rapid, sensitive and reproducible. It can be used to study the toxicokinetics of vinorelbine tartrate micelle in Beagle dogs for injection. After intravenous administration of vinorelbine tartrate micelles in Beagle dogs, AUC_{0-72 h} and C_max were positively correlated with the dose.

科技部“重大新药创制”科技重大专项（2015ZX09501004-002-003）