摘要
目的建立准确可靠的大鼠、比格犬体内紫杉醇(paclitaxel,PTX)血药浓度的超高效液相色谱-串联质谱(UPLC-MS/MS)含量测定方法,对大鼠尾静脉注射、比格犬静脉滴注泰素Ⓡ(TaxolⓇ)注射液和载紫杉醇的D-α-生育酚聚乙二醇1000琥珀酸酯(D-α-tocopheryl polyethylene glycol 1000 succinate,TPGS)修饰的羧甲基壳聚糖(carboxymethyl chitosan,CMCS)-大黄酸(rhein,Rh)偶联物(PTX/TPGS-CR)纳米胶束后的药动学进行研究。方法测定PTX/TPGS-CR胶束与0.9%氯化钠注射液、质量分数5%葡萄糖注射液输液配伍稳定性。血浆样品采用甲基叔丁基醚进行提取,通过UPLC-MS/MS分析测定大鼠尾静脉注射、比格犬静脉滴注PTX/TPGS-CR胶束和TaxolⓇ后血浆样品中的药物浓度,绘制药-时曲线并计算药动学参数。结果PTX/TPGS-CR胶束在0.9%氯化钠注射液复溶后8 h内粒径均无明显变化,无沉淀现象,粒径和多分散系数(polydispersity,PDI)较小。PTX/TPGS-CR胶束在大鼠和比格犬体内均符合三室模型分布。在大鼠体内,PTX/TPGS-CR胶束与TaxolⓇ的生物半衰期(biological half-life,t1/2)分别是70.93、4.98 h。与TaxolⓇ相比,PTX/TPGS-CR胶束的t1/2、平均滞留时间(mean residence time,MRT)明显延长,药-时曲线下面积(area under the cure,AUC)显著增加,分布更广且清除率(clearance,CL)更低,初步验证了PTX/TPGS-CR胶束在体内的长循环特征,并且能够提高PTX的生物利用度;在比格犬体内药动学结果显示,PTX/TPGS-CR胶束与TaxolⓇ的t1/2分别是113.09、30.37 h,MRT0-∞分别为145.02、35.78 h,PTX/TPGS-CR胶束也能延长PTX在比格犬体内的t1/2和MRT。结论PTX/TPGS-CR胶束能明显改善PTX在体内的药动学特征。
OBJECTIVE To establish an accurate and reliable method for determination of blood concentration of paclitaxel(PTX)in rats and Beagle dogs by ultra-high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)and study the pharmacokinetics of TaxolⓇ.METHODS The compatibility stabilities of PTX/TPGS-CR micelles with 0.9%sodium chloride injection and 5%glucose injection were determined.The plasma samples were extracted with methyl tert-butyl ether,and the drug concentrations in the plasma samples were determined by UPLC-MS/MS after tail vein injection in rats,intravenous infusion of PTX/TPGS-CR micelles and TaxolⓇin Beagle dogs,and drug concentration-time curves were obtained.Pharmacokinetic parameters were calculated.RESULTS The particle size of PTX/TPGS-CR micelles did not change significantly within 8 h after reconstitution in 0.9%sodium chloride injection,and there was no precipitation phenomenon,and the particle size and PDI were small.PTX/TPGS-CR micelles conformed to the three-compartment model distribution in rats and Beagle dogs.In rats,the biological half-lives(t1/2)of PTX/TPGS-CR micelles and TaxolⓇwere 70.93 h and 4.98 h,respectively.Compared with TaxolⓇ,PTX/TPGS-CR micelles showed significantly longer t1/2,mean retention time(MRT),significantly increased area under the curve(AUC),wider distribution and lower clearance(CL).The long-circulating characteristics of PTX/TPGS-CR micelles in vivo were preliminarily verified,and the bioavailability of PTX could be improved.In Beagle dogs,the t1/2 of PTX/TPGS-CR micelles and TaxolⓇwere 113.09 h and 30.37 h,and the MRT0-∞were 145.02 h and 35.78 h,respectively.PTX/TPGS-CR micelles could also prolong the t1/2 and MRT of PTX in Beagle dogs.CONCLUSION PTX/TPGS-CR micelles can significantly improve the pharmacokinetics of PTX in vivo.
作者
陆伟利
欧阳惠枝
李崇仙
许雪雅
郑雅玲
王晓颖
徐伟
LU Weili;OUYANG Huizhi;LI Chongxian;XU Xueya;ZHENG Yaling;WANG Xiaoying;XU Wei(College of Pharmacy,Fujian University of Traditional Chinese Medicine,Fuzhou 350122,China)
出处
《中国药学杂志》
CAS
CSCD
北大核心
2023年第17期1573-1581,共9页
Chinese Pharmaceutical Journal
基金
国家自然科学基金资助项目资助(81603301)
福建省科技厅引导性项目资助(2020Y0050)。
