雷替曲塞持续动脉灌注化疗的药代动力学研究

Pharmacokinetic study of Raltitrexed under continuing transarterial infusion

目的于动物模型中测定雷替曲塞动脉持续灌注化疗期间给药动脉/回流静脉及外周静脉的血药浓度,分析雷替曲塞在动物体内的药代动力学特征,为临床应用奠定基础。方法 8头小型猪,随机分为低浓度组和高浓度组,经髂内动脉近端给药,于髂内动脉远端及髂内静脉、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,高效液相色谱仪分析血药浓度。结果随着动脉持续给药时间的延长,两组髂内动脉内的血药浓度都迅速达到最高值,并且峰值变化波动范围不大,最高峰值分别为161.5μg/L,631.5μg/L,药时曲线下面积(area under curve AUC)分别为285.6μg/L·h,1 078.3μg/L·h。随着动脉持续给药时间的延长,两组髂内静脉内的血药浓度都逐渐缓慢上升,给药结束时达到最高值,动脉给药结束后血药浓度迅速下降。外周静脉血的血药浓度未检出。结论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血药浓度,且外周血中浓度极低,更有利于提高局部肿瘤药物浓度直接杀死肿瘤细胞,降低全身不良反应。

Objective To determine the pharmacokinetics of raltitrexedunder transarterial infusion in administrating artery/veins and peripheral venous, to lay the foundation for clinical application. Methods 8 miniature swines were ran domly divided into groups of low concentration and a high concentration group, the agent was administrated from proxi- mal of internal iliac artery,and blood samples were draw from distal of internal iliac artery and internal iliac vein, pe ripheral venous. Blood samples were extracted by solid phase,raltitrexed was analysised by HPLC. Results With the extension of transarterial continuous administration, the plasma concentrations of internal iliac arteries are quickly reached the highest value, and continued with the extension of arterial administration, the peak changed within little range,AUC were 285.6 ~g/L~ h and 1 078.3 /xg/L ~ h. The peak values was 161.5 /~g/L and 631.5 /xg/L. With the extension of administrating time,concentration in internal iliac blood were gradually arise, reached the highest value at the end of the administration,the blood concentration decreased rapidly after the intraarterial administration. Peripheral Blood Blood concentration was not detected. Conclusion Transarterial infusion can retain enough high concentration within the local tissue blood and very low peripheral blood concentration,which help to improve local tumor drug con- centration while reduce systemic adverse reactions.