UPLC-MS/MS检测大鼠血浆中阿帕替尼的浓度及其药动学研究
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摘要
目的采用UPLC-MS/MS建立快速检测大鼠血浆中阿帕替尼浓度的方法,并应用于药动学研究。方法大鼠血浆样本用乙腈沉淀蛋白,液质联用技术检测浓度,流动相为乙腈-水(含0.1%甲酸),梯度洗脱,流速为0.3 mL·min~(-1),柱温40℃,内标为氯唑沙宗;质谱条件:电喷雾离子化源(ESI),负离子监测模式,检测离子对阿帕替尼为m/z396.2→210.0和m/z 396.2→158.0,氯唑沙宗m/z 168.0→132.0。结果阿帕替尼和内标氯唑沙宗的保留时间分别为1.07 min和1.40 min,线性范围为10～2 000 ng·mL~(-1)(r2=0.993),检测限为1 ng·mL~(-1),准确度为90.65%～111.50%,基质效应为89.14%～104.65%,平均回收率>86%,日内、日间精密度RSD均<10%。常温下放置24 h、冻融2次和-80℃冻存30 d的RSD均<10%。药动学研究结果显示,大鼠单次灌胃阿帕替尼76.5mg·kg~(-1),AUC(0-t)为(6114.41±645.99)ng·mL~(-1)·h, CLz/F为(12.21±1.08)L·h-1·kg~(-1),Vz/F为(75.70±38)L·kg~(-1),T1/2为(4.23±1.94)h,Tmax为(2±0.71)h,Cmax为(1 377.7±284.54)μg·L-1。结论该法操作简便,重复性好,准确可靠,适用于大鼠血浆中阿帕替尼的浓度检测及其药动学研究。
OBJECTIVE To establish a UPLC-MS/MS method for rapid determination of apatinib concentration in rat plasma and apply to pharmacokinetics study. METHODS Rat plasma samples were prepared with acetonitrile to precipitate the protein. The apatinib concentration in rat plasma was determined by liquid chromatography-mass spectrometry. The mobile phase was acetonitrile-water(containing 0.1% formic acid). Gradient elution with a flow rate of 0.3 mL·min~(-1), column temperature was 40 ℃, chlorzoxazone was used as internal standard. Mass spectrometry conditions: Electrospray ionization source(ESI), negative ion detection mode, detection pairs were m/z 396.2→210.0 and m/z 396.2→158.0 for apatinib, m/z 168.0→132.0 for chlorzoxazone. RESULTS The retention time of apatinib and internal standard chlorzoxazone were 1.07 min and 1.40 min, respectively. The linear range was 10 to 2 000 ng·mL~(-1)(r2=0.993) and the limit of quantification was 1 ng·mL~(-1). The accuracy of the method was in the range of 90.65 %-111.50 %, and the matrix effect was 89.14 %-104.65 %. Mean recoveries of apatinib in rat plasma were >86%. RSD of intra-day and inter-day precision were both <10%. The RSDs of stabilities of 24 h kept in room temperature, froze-thaw 2 times, 30 d froze in-80 ℃ were all<10 %. Pharmacokinetic study showed that after the rats received a single administration of apatinib with 76.5 mg·kg~(-1), the AUC(0-t) was(6 114.41±645.99)ng·mL~(-1)·h, and CLz/F was(12.21±1.08)L·h-1·kg~(-1), Vz/F was(75.70±38)L·kg~(-1), T1/2 was(4.23±1.94)h, Tmax was(2±0.71)h, Cmax was(1 377.7±284.54)μg·L-1. CONCLUSION The method established is easy to operate, reproducible, accurate and reliable. It is suitable for the determination of apatinib concentration in plasma and can applied to its pharmacokinetics study.
OBJECTIVE To establish a UPLC-MS/MS method for rapid determination of apatinib concentration in rat plasma and apply to pharmacokinetics study. METHODS Rat plasma samples were prepared with acetonitrile to precipitate the protein. The apatinib concentration in rat plasma was determined by liquid chromatography-mass spectrometry. The mobile phase was acetonitrile-water(containing 0.1% formic acid). Gradient elution with a flow rate of 0.3 mL·min~(-1), column temperature was 40 ℃, chlorzoxazone was used as internal standard. Mass spectrometry conditions: Electrospray ionization source(ESI), negative ion detection mode, detection pairs were m/z 396.2→210.0 and m/z 396.2→158.0 for apatinib, m/z 168.0→132.0 for chlorzoxazone. RESULTS The retention time of apatinib and internal standard chlorzoxazone were 1.07 min and 1.40 min, respectively. The linear range was 10 to 2 000 ng·mL~(-1)(r2=0.993) and the limit of quantification was 1 ng·mL~(-1). The accuracy of the method was in the range of 90.65 %-111.50 %, and the matrix effect was 89.14 %-104.65 %. Mean recoveries of apatinib in rat plasma were >86%. RSD of intra-day and inter-day precision were both <10%. The RSDs of stabilities of 24 h kept in room temperature, froze-thaw 2 times, 30 d froze in-80 ℃ were all<10 %. Pharmacokinetic study showed that after the rats received a single administration of apatinib with 76.5 mg·kg~(-1), the AUC(0-t) was(6 114.41±645.99)ng·mL~(-1)·h, and CLz/F was(12.21±1.08)L·h-1·kg~(-1), Vz/F was(75.70±38)L·kg~(-1), T1/2 was(4.23±1.94)h, Tmax was(2±0.71)h, Cmax was(1 377.7±284.54)μg·L-1. CONCLUSION The method established is easy to operate, reproducible, accurate and reliable. It is suitable for the determination of apatinib concentration in plasma and can applied to its pharmacokinetics study.
引文
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[12]CHEN L T,OH D Y,RYU M H,et al.Anti-angiogenic therapy in patients with advanced gastric and gastroesophageal junction cancer:A systematic review[J].Cancer Res Treat,2017,49(4):851-868.
[2]TIAN S,QUAN H,XIE C,et al.YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo[J].Cancer Science,2011,102(7):1374-1380.
[3]ZHAO D Z,HOU H L,ZHANG X C.Progress in the treatment of solid tumors with apatinib:a systematic review[J].Onco Targets Ther,2018(11):4137-4147.
[4]SCOTT L J.Correction to apatinib:A review in advanced gastric cancer and other advanced cancers[J].Drugs,2018(12):1-12.
[5]TEO Y L,HO H K,CHAN A.Metabolism-related pharmacokinetic drug-drug interactions with tyrosine kinase inhibitors:current understanding,challenges and recommendations[J].Br J Clin Pharmacol,2015,79(2):241-253.
[6]TYLER T.Drug interactions in metastatic breast cancer[J].JOncol Pharm Pract,2011,17(3):236-245.
[7]KO Y,TAN S L,CHAN A,et al.Prevalence of the coprescription of clinicallyvimportant interacting drug combinations involving oral anticancer agents in Singapore:a retrospective database study[J].Clin Ther,2012,34(8):1696-1704.
[8]LIU X,ZHANG Y,CHEN Q,et al.Pharmacokinetic drug interactions of apatinib with rifampin and itraconazole[J].JClin Pharmacol,2017,58(8):1-10.
[9]DING J,CHEN X,GAO Z,et al.Metabolism and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor apatinib in humans[J].Drug Metab Dispos,2013,41(6):1195-1210.
[10]LIN D,WANG Z,LI J,et al.The Effect of apatinib on the metabolism of carvedilol both in vitro and in vivo[J].Pharmacology,2016,97(1-2):31.
[11]LOU D,QIAO L M,CHENG C,et al.Determination and pharmacokinetic study of apatinib in rat plasma by UPLC[J].JChromatogr Sci,2015,54(1):17.
[12]CHEN L T,OH D Y,RYU M H,et al.Anti-angiogenic therapy in patients with advanced gastric and gastroesophageal junction cancer:A systematic review[J].Cancer Res Treat,2017,49(4):851-868.