目的 建立測定比格犬血漿中酒石酸長春瑞濱濃度的LC-MS/MS方法并用于毒代動力學(xué)研究。方法 選擇12只比格犬分為3組，分別給予0.29、0.58、1.174 mg/kg注射用長春瑞濱膠束，分別于給藥前及給藥后0.03、0.25、0.5、1、2、4、8、12、24、48、72 h采集血樣；用蛋白沉淀法處理血漿，采用API4000三重四極桿串聯(lián)質(zhì)譜儀測定濃度，離子化方式為電噴霧－正離子（ESI），監(jiān)測方式為多反應(yīng)監(jiān)測，酒石酸長春瑞濱監(jiān)測離子對m/z 779.3/122.4，蘭索拉唑（IS）監(jiān)測離子對m/z 392.0/188.1。色譜柱為inertsil ODS-3（50 mm×4.6 mm，5 μm），流動相為甲醇-5.0 mmol/L乙酸銨（含0.02%甲酸）梯度洗脫，體積流量為0.3 mL/min，柱溫為35℃。結(jié)果 酒石酸長春瑞濱在1～1 000 ng/mL線性關(guān)系良好（r²=0.997 9）；定量限為1.0 ng/mL，回收率為104.38%～106.15%，基質(zhì)效應(yīng)為98.31%～107.37%，日間精密度為4.43%～8.92%，日內(nèi)精密度為2.20%～8.40%。低、中、高劑量組AUC_{0~72 h}分別為（163.6±153.6）、（200.4±50.7）、（388.4±266.6）μg/L·h，峰濃度（C_max）分別為（142.9±127.0）、（198.4±107.8）、（442.5±259.9）μg/L。結(jié)論 本法簡單、快速、靈敏度高、重復(fù)性好，可用于注射用酒石酸長春瑞濱膠束比格犬體內(nèi)毒代動力學(xué)研究。比格犬靜脈注射給予注射用酒石酸長春瑞濱膠束后，AUC_{0~72 h}及C_max與劑量均呈正相關(guān)。

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“重大新藥創(chuàng)制”科技重大專項（2015ZX09501004-002-003）