载药微球三氧化二砷治疗兔VX2肝肿瘤药代动力学研究

Pharmacokinetics of drug-eluting beads loading arsenic trioxide in the treatment of rabbit VX2 liver tumour

目的观察经肝动脉导管化疗栓塞术(TACE)中应用载药栓塞微球(CalliSpheresBeads,CB,江苏恒瑞)加载三氧化二砷(arsenictrioxide,ATO)对兔VX2肝肿瘤的化疗栓塞作用及其药代谢动力学。方法64只荷瘤兔采用数字表法随机分为4组,对照组、空白微球栓塞组(CB组)、ATO载药微球栓塞组(CBATO组)、ATO碘油栓塞组(cTACE组)。TACE术前、术后10、20、40min及1、3、6、12h,1、3d取血并检测血ATO浓度及肝肾功能指标。TACE术后1、3、7、14d处死实验兔4只,取肿瘤组织、肝脏、肾脏、肺、心脏和肌肉标本采用氢原子荧光方法检测ATO浓度。采用双侧t检验比较CBATO组与cTACE组的血及组织的ATO浓度及肝肾功能。结果术后1、3、7d对照组谷氨酸转氨酶(ALT)和天冬氨酸氨基转移酶(AST)水平无明显变化,CB组、CBATO组和cTACE组ALT和AST水平升高(ALT的F值分别为25.872、17.69、7.016,AST的F值分别为46.365、32.385、12.548,P值均<0.05),且与对照组相比差异有统计学意义;术后1、3、7d,CBATO组ALT和AST水平低于cTACE组,但差异无统计学意义(ALT的t值分别为0.369、0.432、0.169,AST的t值分别为0.353、0.488、0.593,P值均>0.05)。在各观测时间点,4组实验兔的尿素氮及血肌酐水平差异无统计学意义。术后10、20min时CBATO组的血ATO较cTACE组低,差异有统计学意义(t值分别为7.675、6.461,P值均<0.01);术后12h后CBATO组的血ATO高于cTACE组。在活性瘤组织内,CBATO组ATO浓度较cTACE组高,术后1d两者差异无统计学意义(t值为2.155,P=0.068),术后3、7、14d差异有统计学意义(t值分别为11.462、7.624、2.649,P值均<0.05)。结论载药微球可以在肿瘤组织中持续缓慢释放化疗药物,较长时间保持肿瘤组织内化疗药物较高浓度,并没有增加实验兔的肝肾毒性。

Objective To study pharmacokinetics and tissue distribution of Calli Spheres Beads (CB) loaded Arsenic trioxide (ATO) on rabbit VX2 liver tumor by transcatheter arterial chemoembolization (TACE). MethodSixty four rabbits with VX2 liver tumors were randomly divided into 4 groups:control group,CB group,CBATO group and cTACE group. Blood samples were taken at specific time points after TACE.The blood concentration of ATO,liver and kidney functions were examined respectively. In each group,every 4 rabbits were sacrificed on 1 days,3 days,7 days and 14 days after operation. The tumor,liver,kidney,lung,heart and muscle were taken to detect the drug concentration. Bilateral t-test was used to compare the drug concentration in blood and tissue between CBATO group and cTACE group. Results Statistically,The levels of ALT and AST in group CBATO and cTACE on 1st,3rd and 7th days after TACE were significantly higher than those in CB group(ALT:F=25.872, 17.69, 7.016, AST:F=46.365, 32.385, 12.548, P<0.05) respectively. The ALT and AST levels in CBATO group were statistically lower than those in cTACE group (ALT:t=0.369, 0.432, 0.169, 0.353,AST:t=0.488, 0.593, P>0.05). There were no statistically significant differences in the levels of BUN and Scr between the four experimental groups at each observation time point. Statistically,10 minutes and 20 minutes after TACE,the blood drug concentration inCBATO was significantly lower than that in cTACE (t=7.675, 6.461, P<0.001). while 12 hours after operation,blood drug concentration in CBATO group was higher than that in cTACE group. In tumor tissue,the concentration of ATO in CBATO was higher than that in cTACE,and there was no statistical differences on the 1st day after TACE (t=2.155, P=0.068),but there was a statistical differences between 3rd,7th and 14th days (t=11.462,7.624, 2.649, P<0.05). Conclusion CBATO could prolong the time of drug metabolism,increase the drug concentration in tumor tissue,and didn′t aggravate the damage of liver and kidney function.