经淋巴管灌注卡铂脂质体的药代动力学实验研究

目的 :研究卡铂脂质体 (CPL)经淋巴管内灌注 (ILVP)的体内药代动力学。方法 :随机将 6 0只雌性新西兰白兔分为 3组 :ILVP组 ,经兔窝淋巴结输出管穿刺置管给药 ;腹腔内注射 (IPI)组及静脉内注射 (IVI)组。每只给予CPL 30ml混悬液 ,存活 16 8h后处死。用石墨炉原子吸收分光光度法测定每组各时点的外周血及盆腔腹膜后淋巴结组织中铂总 (Pt)浓度 ,并摘取兔淋巴结及心、肝、脾、肾组织作病理学检查CPL的毒性作用。结果 :ILVP组淋巴结铂峰最大浓度 (Cmax)为 6 8.4 μg/g(湿重 ) ,药时曲线下面积 (AUC)为2 117.5 μg·h/g(湿重 ) ,外周血铂Cmax为 12 .8μg/ml,AUC为 2 10 .6 μg·h/ml ;IPI组淋巴结铂Camx为 35 .2 μg/g(湿重 ) ,AUC为 94 4 .2 μg·h/g(湿重 ) ,外周血铂Cmax为 11.4 μg/ml,AUC为 2 76 .3μg·h/ml;IVI组淋巴结铂Cmax为 18.4 μg/g(湿重 ) ,AUC为 319.9μg·h/g(湿重 ) ,外周血铂Cmax为 4 0 .7μg/ml,AUC为 6 6 8.0 μg·h/ml。各实验组间兔淋巴结铂浓度分布差异有显著性 (P <0 .0 5 )。其中ILVP组淋巴结铂Camx是IPI组的 1.9倍 (P =0 .0 4 ) ,是IVI组的 3.7倍 (P =0 .0 13)。外周血中铂浓度 :IVI组高于ILVP组 (P =0 .0 4 4 ) ,但IPI组与ILVP组差异无显著性 (P =0 .6 3)。淋巴结病理形态学检

The experimental study on in vivo pharmacokinetics of carboplatin liposomes via intralymphatic vessel perfusion.

Objective:To study on in vivo pharmacokinetics of carboplatin liposomes (CPL) after intralymphatic vessel perfusion (ILVP) with animal experiment.Methods:Sixty female health rabbits,which would be killed after administrating CPL 30mg at most living 168 hours,were randomly divided into three groups,ILVP group in which drug was given via catheterization in efferent vasa of lymphnode of popliteal fossa,intraperitoneal injection (IPI) group and intravenous injection (IVI) group.Then,in various time point of serum and lymphnodes,platinum concentration was measured by graphite stove atomic absorption spectrophotometry.Some selected lymphnodes,heart,liver,spleen,kidney tissues were pathologically checked for the purpose of confirming cytotoxic effect of CPL.Results: The peak concentration of total platinum (Cmax) in lymphnodes and the area under platinum concentration curve (AUC) were 68.4μg/g of moist weight (MW),2117.5μg·h/g(MW) in ILVP group,35.2μg/g (MW),944.2μg·h/g (MW) in IPI group and 18.4μg/g (MW),319.9 μg·h/g (MW) in IVI group,respectively,which revealed significant differences among groups (P<0.05).Lymphnodes concentration of total platinum in ILVP group was as 1.9 times as that in IPI group (P=0.04) and as 3.7 times as that in IVI group (P=0.013).The serum concentration of total platinum and AUC of groups in the same order were 12.8μg/ml,210.6μg·h/ml,11.4μg/ml,276.3μg·h/ml and 40.7μg/ml,668.0μg·h/ml respectively.Serum level of platinum was obviously higher in IVI group than that in IPI group as well as ILVP group (P<0.05).However,no differences of platinum concentration were found between ILVP group and IVI group (P=0.074).Lymphocytes degeneration and necrosis or structural disorders were found by histological examination in ILVP group and IPI group,which were more obvious in ILVP group.Nevertheless,the pathological changes of heart,liver,spleen and kidney were slight or absent in ILVP group. Conclusions:CPL via ILVP has obvious targeting to retro peritoneal lymphnodes of pelvic cavity,which is more effective than that via IPI or IVI.This study has important significance for guiding treatment of gynecologic malignant neoplasms with lymph metastases.