摘要
目的:建立LC-MS/MS法同时测定大鼠血浆中辛伐他汀和辛伐他汀酸浓度,并考察单剂量五酯胶囊对辛伐他汀及辛伐他汀酸在大鼠体内药代动力学影响。方法:采用简单的液液萃取法(LLE),以洛伐他汀为内标,选用Agilent Eclipse-C 18(2.1 mm×150 mm,3.5μm)为色谱柱,水(含0.1%甲酸)-乙腈(含0.1%甲酸)(5∶95,V/V)为流动相。采用喷雾电离源(ESI);正离子方式检测,扫描方式为多反应监测(MRM)。将12只雄性大鼠随机分成对照组和实验组,每组6只。对照组灌胃给予辛伐他汀40 mg/kg,实验组先灌胃给予五酯胶囊内容物150 mg/kg(每粒含五味子甲素11.25 mg),15 min后,再灌胃给予辛伐他汀40 mg/kg,两组分别于给药前和给药后时间点0.25、0.5、0.75、1.0、2.0、3.0、4.0、6.0、8.0、12.0 h于大鼠眼眶静脉丛采血约0.5 mL于肝素管中。通过Phoenix软件计算得到相关药代动力学参数。结果:血浆中的辛伐他汀、辛伐他汀酸分别在5~5000 ng/mL内线性关系良好(辛伐他汀r=0.9940,辛伐他汀酸r=0.99454),最低定量下限分别为5 ng/mL,日内标准偏差与日间标准偏差均小于10%,提取回收率可达80%以上。主要药代动力学参数如下(对照组与实验组),C max[(97±24)vs.(590±227)ng/mL,(385±137)vs.(1322±502)ng/mL]、AUC 0-t[(446±70)vs.(1315±535)ng·h·mL-1,(1305±531)vs.(3393±1047)ng·h·mL-1]、t 1/2[(2.37±0.18)vs.(2.93±0.78)h,(2.39±0.43)vs.(3.44±0.80)h]明显增加,差异均有统计学意义(P<0.05)。结论:本实验建立的LC-MS/MS法快捷、简单、灵敏、专属性强,适用于大鼠血浆中辛伐他汀和辛伐他汀酸的测定;五酯胶囊对大鼠体内的辛伐他汀和辛伐他汀酸的药代动力学特征有影响,提示临床两药联用可能会发生显著的相互作用。
AIM:To develop LC-MS/MS method for simultaneous determination of simvastatin and simvastatin acid concentrations in rat plasma,and investigate the pharmacokinetic effects of Wuzhi capsule(WZC)on simvastatin and simvastatin acid concentrations in rats.METHODS:The method was based on simple liquid liquid extraction(LLE)with lovastatin as internal standard.Agilent Eclipse-C 18(2.1 mm×150 mm,3.5μm)was used as the chromatographic column,while water-acetonitrile(both of containing 0.1%formic acid)(5∶95,V/V)was used as the mobile phase.Detection was performed with multiple reactions monitoring(MRM)using electrospray ionization(ESI).Twelve male rats were divided into control group and experimental group,with 6 rats in each group.The control group was given 40 mg/kg simvastatin by gavage,and the experimental group was given 150 mg/kg Wuzhi capsule(containing deoxyschizandrin 11.25 mg per capsule)by gavage and followed by 40 mg/kg simvastatin by gavage after 15 minutes.About 0.5 mL of blood was collected from the orbital vein plexus of rats in heparin tube at the time points of 0.25,0.5,0.75,1.0,2.0,3.0,4.0,6.0,8.0 and 12.0 hours before and after administration,respectively.The relevant pharmacokinetic parameters were calculated by Phoenix software.RESULTS:The calibration curves of simvastatin and its metabolite simvastatin acid showed a good linearity over the concentration range of 5-5000 ng/mL with the lower limit of quantitation of 5 ng/mL(simvastatin r=0.9940,simvastatin acid r=0.99454).The intra-day and inter-day relative standard deviations were both below 10%,and the absolute recovery could reach more than 80%.The major pharmacokinetic parameters were as follows(control group vs.experimental group),C max[(97±24)vs.(590±227)ng/mL,(385±137)vs.(1322±502)ng/mL],AUC 0-t[(446±70)vs.(1315±535)ng·h·mL-1,(1305±531)vs.(3393±1047)ng·h·mL-1)],t 1/2[(2.37±0.18)vs.(2.93±0.78)h,(2.39±0.43)vs.(3.44±0.80)h]increased significantly(P<0.05).CONCLUSION:The LC-MS/MS method established in this study is fast,simple,sensitive and specific,and is suitable for the determination of simvastatin and simvastatin acid in rat plasma.Wuzhi capsule could affect the pharmacokinetic parameters of simvastatin and simvastatin acid in rats.It is suggested that the combination of two drugs in clinical practice will cause significant interaction.
作者
孙青
孙建芳
李力
常会超
周权
SUN Qing;SUN Jianfang;LI Li;CHANG Huichao;ZHOU Quan(School of Pharmacy,Zijingang Campus,Zhejiang University,Hangzhou 310012,Zhejiang,China;Medical Technology Support Department of Qinhuai Medical District,General Hospital of Eastern Theater Command,Nanjing 210002,Jiangsu,China;Department of Pharmacy,Zhejiang Hospital,Hangzhou310013,Zhejiang,China;Department of Pharmacy,the Second Affiliated Hospital of Zhejiang University School of Medicine,Hangzhou 310009,Zhejiang,China)
出处
《中国临床药理学与治疗学》
CAS
CSCD
2020年第11期1242-1249,共8页
Chinese Journal of Clinical Pharmacology and Therapeutics
基金
浙江省自然科学基金资助项目(LQ15H310003)。
