摘要：
目的 分析经不同介入途径或方式给予雷替曲塞对实验兔肝功能、组织学及药代动力学(药动学)的影响,探讨临床局部应用雷替曲塞的可行性、安全性及优势.方法将新西兰大白兔25只随机等分为外周静脉注射组(A组)、肝动脉灌注组(B组)、肝动脉碘化油栓塞组(C组)、肝动脉明胶海绵颗粒栓塞组(D组)及肝脏直接穿刺注射组(E组).每只兔均接受临床等效剂量(0. 17mg/kg体质量)雷替曲塞注射液.抽取实验兔给药后5、15、30、60、120、180 min静脉血作药动学分析,检测给药后6 h及1周肝功能,并制作同时段肝脏组织学标本.结果A组给药后5、60 min时实验兔外周血药浓度分别为0. 91、0 μg/mL,B组5、180 min时分别为1. 73、0. 37 μg/mL,C组5、180 min时分别为0. 82、0. 08 μg/mL,D组5、180 min时分别为0. 94、0. 08 μg/mL,E组5、60 min时分别为0. 39、0. 13 μg/mL.给药后6 h C组、D组、E组血清天冬氨酸转氨酶(AST)、谷氨酸转氨酶(ALT)明显升高(P＜0. 01),术后1周时已恢复接近正常.肝组织变性坏死程度为E组＞C组＞D组＞B组＞A组,E组周围正常肝组织未见明显坏死.结论兔肝对雷替曲塞无明显首过清除效应,临床等效剂量雷替曲塞经肝动脉给药后肝细胞损伤较明显,直接穿刺注射对肝脏损伤较局限,临床上可根据超选择插管程度及肿瘤大小调整应用剂量.%Objective To assess the influence of different interventional injection routes of raltitrexed on the liver function, histology and pharmacokinetics in experimental rabbits, and to discuss the feasibility, safety and advantages of local application of raltitrexed. Methods A total of 25 New Zealand white rabbits were randomly and equally divided into 5 groups with 5 rabbits in each group: group A (using peripheral intravenous injection), group B (employing hepatic arterial infusion), group C (adopting hepatic artery embolization with Lipiodol), group D (hepatic artery embolization with gelfoam particles), and group E (direct puncture of liver and injection). Clinical equivalent dose (0. 17 mg/kg) raltitrexed injection was given to each experimental rabbit. At 5, 15, 30, 60, 120 and 180 min after the treatment, venous blood sample was collected for pharmacokinetic analysis. At 6 h and one week after administration of drug, liver functions were tested, and histological specimens of liver tissues were made at the same time. Results The peripheral blood drug concentrations at 5 and 60 min in group A were 0. 91 μg/mL and 0 μg/mL respectively, at 5 and 180 min in group B were 1. 73 μg/mL and 0. 37 μg/mL respectively, at 5 and 180 min in group C were 0. 82 μg/mL and 0. 08 μg/mL respectively, at 5 and 180 min in group D were 0. 94 μg/mL and 0. 08 μg/mL, and at 5 and 60 min in group E were 0. 39 μg/mL and 0. 13 μg/mL respectively. Six hours after administration of drug, the serum levels of AST, ALT in group C, group D and group E were significantly increased (P＜0. 0l), which returned to normal levels in one week after the treatment. The severity of liver tissue degeneration and necrosis detected in each group varied, in a severity - decreasing order, from group E, group C, group D, group B and group A. In group E, the surrounding normal liver tissue had no obvious necrosis. Conclusion The rabbit' s liver has no significant first pass elimination effect to raltitrexed. The equivalent dose of raltitrexed administered through the hepatic artery can cause obvious hepatocellular injury. Direct puncture and injection produce limited liver injury. Clinically, the dose of raltitrexed can be adjusted based on the degree of super selective catheterization condition and tumor size. (J Intervent Radiol, 2018, 27:247-251)
