动脉持续灌注化疗中雷替曲塞的药代动力学特征

Abstract

目的:通过检测雷替曲塞经猪肝动脉持续灌注化疗期间给药动脉下游及外周血内血药浓度,分析雷替曲塞在猪体内的局部及全身的药代动力学特征.方法:24头猪随机分为1 mg组和4 mg组,采用30、60及120 min持续给药方案,经肝总动脉近端给药,于肝动脉下游、外周静脉分别采集血液标本,采用固相萃取法提取血浆样品中的雷替曲塞,高效液相色谱仪测定血药浓度.结果:各剂量组及时间组中,给药动脉下游内的血药浓度都迅速达到最高值,并且维持在相对稳定状态,1 mg剂量下30、60及120 min靶动脉内Cmax分别为(405.4 ± 83.8)、(212.0 ± 25.4)和(128.3 ± 32.2) μg?L-1;4 mg剂量下30、60及120 min靶动脉内Cmax分别为:(1601.9 ± 259.6)、(902.1 ± 104.2)和(587.3 ± 160.4) μg?L-1.外周静脉内,1 mg剂量组30 min组Cmax为(104.8 ± 18.3)μg?L-1;4 mg剂量组30、60 min组Cmax分别为(271.1 ± 52.7)和(157.7 ± 34.6)μg?L-1.结论:雷替曲塞动脉持续灌注化疗可以在足够的时间内保持局部组织内较高的药物浓度和较低的外周血药浓度,延长给药时间可以保证局部血药浓度并降低外周血药浓度,减少毒性.

Objective: By detecting blood concentration of raltitrexed in proximal artery and peripheral vein in swine model to analyze the pharmacokinetic characteristics of raltitrexed during continuous infusion via hepatic artery. Methods: Twenty-four swine were randomly divided into 1 mg dosage group and 4 mg dosage group, and raltitrexed was infused within 30, 60 and 120 min respectively. Blood samples were collected in the proximal hepatic artery and the peripheral veins respectively. The samples were extracted by solid phase extraction and tested by DHPLC. Results: Plasma concentration in the proximal arteries rapidly reached the highest value in each dosage/time group, and maintained at a relatively stable state until the end of administration, Cmaxat 30, 60 and 120 min in 1 mg group were (405.4±83.8), (212.0±25.4) and (128.3±32.2) μg?L-1respectively, and those in 4 mg group were (1 601.9±259.6), (902.1±104.2) and (587.3±160.4) μg?L-1respectively. As for peripheral vein, Cmaxat 30, 60 min groups were (104.8±18.3) and (61.4±7.1) μg?L-1in 1 mg group and (271.1±52.7) and (157.7±34.6) μg?L-1in 4 mg group respectively. Conclusion: Transarterial continuous infusion chemotherapy could maintain higher plasma concentration for a sufficient period of time in local organ and peripheral vein, and longer administration time could lead to suitable concentration for intrahepatic lesions and extrahepatic lesions.