微透析联合UPLC-MS/MS研究丹参酮ⅡA在大鼠脑脊液中的药动学  

Pharmacokinetics of TanshinoneⅡA in Rats Cerebrospinal Fluid by Microdialysis Combined with UPLCMS/MS

作　　者：张勋[1] 吕贵杰 陈艳成 刘珂 徐伟[1] 王晓颖[1] 林羽[1] ZHANG Xun;LYU Guijie;CHEN Yancheng;LIU Ke;XU Wei;WANG Xiaoying;LIN Yu(College of Pharmacy,Fujian University of Traditional Chinese Medicine,Fuzhou 350122,China)

机构地区：[1]福建中医药大学药学院,福州350122

出　　处：《中国现代应用药学》2024年第22期3053-3060,共8页Chinese Journal of Modern Applied Pharmacy

基　　金：国家自然科学基金项目(81674046);福建中医药大学基础类学科科研提升计划项目(XJC2022007)。

摘　　要：目的应用在体脑微透析联合UPLC-MS/MS探究丹参酮ⅡA(tanshinone IIA,TSA)在正常大鼠及脑缺血/再灌注(cerebral ischemia reperfusion injury,CIRI)损伤模型大鼠脑脊液中的药动学特征。方法采用增量法和减量法考察灌流液流速和TSA的质量浓度对回收率和相对释放率的影响;减量法测定探针在大鼠体内相对释放率,考察其8 h内的稳定性。应用UPLC-MS/MS技术分析大鼠在体脑透析液样品中TSA浓度,绘制脑透析液药物浓度-时间曲线,计算药动学参数。结果探针体外回收率和相对释放率基本一致,且随灌流速度的增大而减小,与TSA的浓度无关;体内相对释放率在1.5~8.0 h内基本保持不变。UPLC-MS/MS方法学考察结果均符合生物样品要求。正常大鼠和大脑中动脉阻塞/再灌注损伤模型大鼠分别腹腔注射TSA后,脑脊液中药物浓度分别在60 min和80 min达到最高值,半衰期均为69.32 min。不同剂量给药后,脑透析液中TSA浓度差异显著(P<0.05),达峰浓度、药时曲线下面积随剂量而升高,平均驻留时间为102.90~170.48 min。结论本研究建立稳定可行的TSA在体脑微透析取样体系和UPLC-MS/MS定量方法,并用于治疗时间窗内TSA脑透析液药动学研究。TSA溶液在正常和模型大鼠脑脊液中分布迅速,病理状态使TSA脑内分布浓度增加。本研究为TSA早期预防和治疗CIRI用药合理性提供依据。OBJECTIVE To investigate the pharmacokinetics of tanshinone IIA(TSA)in vivo normal and cerebral ischemia/reperfusion injury(CIRI)rats cerebrospinal fluid by microdialysis combined with UPLC-MS/MS.METHODS The effects of different perfusion flow rates and TSA concentrations between the relative recovery rate and the relative loss rate were analyzed by incremental and reduction methods.The reduction method was also applied to investigate the stability of the probe recovery rate in 8 h.Cerebral dialysates were collected in normal and middle cerebral artery occlusion/reperfusion rats(MCAO/R)which were injected with TSA internationally.Then content of TSA in samples were quantified by UPLC-MS/MS that was established and verified.Meanwhile,drew the drug time curve and calculated the pharmacokinetic parameters.RESULTS The relative recovery rate and relative loss rate of the microdialysis probe in vitro were nearby.The increased of perfusion velocity,the decreased of the relative recovery rate as well as the relative loss rate.In addition,both of them were independent of TSA concentration.The relative loss rate in vivo was stable between 1.5 and 8.0 h.The methods of UPLC-MS/MS was excellent for the determination of TSA in rats cerebral dialysate.TSA of cerebral dialysates in normal and middle cerebral artery occlusion/reperfusion model rats was up to the highest at 60 min and 80 min respectively,but the half-life was the same of 69.32 min.Its concentration was significantly different(P<0.05)when the rats were intervened by varied doses of TSA.The higher of TSA,the more peak concentration and area under curve.The mean residence times in all groups were 102.90−170.48 min.CONCLUSION The established methods of TSA in microdialysis and UPLC-MS/MS are applied to investigate the kinetic in vivo brain feasibly and accurately within treatment time window.The results indicates that TSA is able to cross the blood-brain barrier and enter the brain fast.The pathological state of CIRI will increase the distribution of TSA in the brai

关 键 词：丹参酮ⅡA 微透析 超高效液相色谱-串联质谱法 脑脊液 药动学 

分 类 号：R969.1[医药卫生—药理学]