目的:建立人血浆中紫杉醇(paclitaxel,PTX)浓度的液相色谱-质谱(liquid chromatography-mass spectometry,LC-MS)检测方法,比较注射用紫杉醇脂质体(paclitaxelliposomeforinjection,L-PTX)和常规紫杉醇注射液(conventional paclitaxel injection,C-PTX)在肿瘤患者中的药动学特征。方法:采用随机、开放和对照的试验设计方案。试验分2组,每组各8例患者,分别静脉滴注175mg/m2L-PTX或C-PTX,并于静脉滴注过程中的1.5和3h及滴注结束后的0.25、0.5、1、2、4、8、12、24、36、48和72h采集受试者血样。LC-MS法测定血药浓度,应用DAS2.0软件计算药动学参数并进行比较。结果:患者单次静脉滴注175mg/m2L-PTX与C-PTX的主要药动学参数:血浆峰浓度(Cmax)分别为6455±2247和7400±1542μg/L;药物血浆浓度-时间曲线下面积(area under the plasma concentration-time curve,AUC0-∞)分别为14812±2846和21693±2657μg·h·L-1;血浆消除半衰期(t1/2z)分别为30.5±7.3和13.7±3.2h;表观分布容积(Vz)分别为526.8±112.1和162.9±49.1L/m2;血浆清除率(plasmaclearance,CLz)分别为12.3±2.7和8.2±1.0L·h-1·m-2。经统计学分析,2组的药动学参数差异有统计学意义(P<0.05)。结论:脂质体包裹后改变了PTX的体内药动学特性,与常规PTX相比,脂质体制剂在肿瘤患者体内的分布特性和消除情况有显著不同,具有更好的组织亲和性与缓释作用。
A sensitive and selective method has been developed and validated for the quantitation of paclitaxel in human plasma by liquid chromatography-electrospray ionization mass spectrometry （LC-ESI-MS）. Paclitaxel and norethindrone （used as internal standard, I.S.） were extracted from human plasma by a one-step liquid-liquid extraction with t-butyl methyl ether. Separation on a Zorbax SB-C18 column （100 mm×2.1 mm, 3.5 μm, Agilent） was achieved by gradient elution with methanol and 0.2 mmol/L ammonium formate containing 0.1% formic acid. The selected-ion monitoring （SIM） targeted ions of [M＋Na] at m/z 876.5 for paclitaxel and [M＋H] at m/z 299.4 for I.S. The assay was validated in the range of 1.0-400 ng/mL （r〉0.998） with LLOQ of 1.0 ng/mL. Intra- and inter-day precisions were all less than 9.0%, with accuracies of ＋6.8%. The method was successfully applied to evaluate the pharmacokinetics of paclitaxel liposome for injection in patients.
