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目的建立一种简便、快速、灵敏的测定比格犬血浆中硫酸长春新碱(vincristine sulfate,VCR)浓度的液相串联质谱(LCMS/MS)法,并研究硫酸长春新碱热敏脂质体(VSTL)比格犬体内药动学特征。方法采用叔丁基甲醚对血浆进行提取,液相分离采用Agela Venusil XBP C18(2.1 mm×30 mm,3.0μm)分析柱,柱温30℃,以甲醇-水为流动相,采用梯度洗脱,流速为0.4m L·min-1,进样量10μL;选用气动辅助电喷雾离子化(ESI),在正离子电离模式下,在多反应监测(MRM)的模式下检测离子对m/z 825.4→807.2(VCR)和m/z 811.3→223.9(硫酸长春碱)。两组比格犬分别静脉推注0.07 mg·kg-1VSTL与硫酸长春新碱注射液,采用高效液相-串联质谱测定比格犬血浆中VCR浓度,计算主要药动学参数并比较研究比格犬注射VSTL与硫酸长春新碱注射液(VSI)的药动学特征。结果血浆中无干扰测定的内源性物质,VCR在0.25~500 ng·m L-1内线性良好(r=0.994 3),定量限为0.25 ng·m L-1,日内、日间精密度(RSD)均小于15%。VSTL和VSI的ρmax分别为(121.00±42.31)、(61±23.36)ng·m L-1;t1/2λz分别为(23.95±9.03)、(37.91±8.02)h;CLz分别为(0.37±0.07)、(0.35±0.09)L·h·kg-1;Vz分别为(12.15±2.14)m L·kg-1、(18.95±3.27)L·kg-1;AUC0-t分别为(144.87±1.10)、(127.7±2.45)ng·h·m L-1。AUC0-∞分别为(152.97±12.56)、(131.61±13.22)ng·h·m L-1。结论 LC-MS/MS方法快速、准确、灵敏,适合于临床前药动学研究。静脉输注VSTL后的ρmax和AUC显著高于VSI,其他药动学参数没有显著差异。
Objective To establish a simple, rapid and sensitive LCMS / MS method for the determination of vincristine sulfate (VCR) in beagle dogs plasma and to study the effect of vincristine sulfate liposomes (VSTL) beagle dogs pharmacokinetic characteristics. Methods The plasma was extracted with tert-butyl methyl ether. The liquid was separated on a column of Agela Venusil XBP C18 (2.1 mm × 30 mm, 3.0 μm). The column temperature was 30 ℃. The mobile phase consisted of methanol and water, Was 0.4m L · min-1, and the injection volume was 10μL. The ion-pair m / z 825.4 was detected under positive ionization mode in multiple reaction monitoring (MRM) mode by using pneumatic assisted electrospray ionization (ESI) 807.2 (VCR) and m / z 811.3 → 223.9 (vinblastine sulfate). The beagle dogs were intravenously injected with 0.07 mg · kg-1 VSTL and vincristine sulfate injection respectively. The plasma concentration of VCR in beagle dogs was determined by high performance liquid chromatography-tandem mass spectrometry. The main pharmacokinetic parameters were calculated and compared with that of Beagle dogs Pharmacokinetic Characteristics of Canine VSTL and Vincristine Sulfate Injection (VSI). Results The endogenous substance with no interference in plasma assay showed good linearity (r = 0.994 3) and a quantitative limit of 0.25 ng · m L-1 for VCR between 0.25 and 500 ng · m L-1. The intra- and inter-day precision (RSD) are less than 15%. The mean ρmax of VSTL and VSI were (121.00 ± 42.31) and (61 ± 23.36) ng · m L-1, respectively, and the values of t1 / 2λz were (23.95 ± 9.03) and (37.91 ± 8.02) ), (0.35 ± 0.09) L · h · kg-1, Vz were (12.15 ± 2.14) m L · kg-1 and (18.95 ± 3.27) L · kg-1 respectively. The AUC0-t were (144.87 ± 1.10 ), (127.7 ± 2.45) ng · h · m L-1. AUC0-∞ were (152.97 ± 12.56) and (131.61 ± 13.22) ng · h · m L-1, respectively. Conclusion The LC-MS / MS method is rapid, accurate and sensitive and suitable for preclinical pharmacokinetic studies. The ρmax and AUC of VSTL after intravenous injection were significantly higher than those of VSI. There was no significant difference in other pharmacokinetic parameters.