持续动脉及静脉注射5-氟尿嘧啶和吡喃阿霉素的药代动力学研究

Pharmacokinetics of consecutive intra-arterial and intravenous infusion of 5-fluorouracil and 4'-O-tetrahydropyranyladriamycin

目的：探讨5-氟尿嘧啶（5-fluorouracil，5-FU）和吡喃阿霉素（4’-O—tetmhydropymnyladriamycin，THP）经髂内动脉及静脉途径持续注射时体内的变化规律和影响因素，为优化盆腔恶性肿瘤动脉化疗提供实验依据。方法：成年新西兰雌兔随机分为2组，一组为将5-FU和THP经髂内动脉持续注射6h，另一组通过耳缘静脉同法注射这2种药物。注射过程中于不同时间点采血样和子宫组织标本，注射完毕后，即处死动物，另取心、肺和盆腔富含淋巴结的脂肪组织。以高效液相色谱（high performance liquid chromatography，HPLC）法测定血清及各组织样本中的药物浓度。结果：动脉注射5-Fu时在血液中的峰浓度和药时曲线下面积（area—under—curve，AUC）值稍低于静脉注射，而在子宫组织中药物的峰浓度是静脉注射的2～3倍，AUC值是静脉注射的3倍，在盆腔淋巴及周围组织中的峰浓度是静脉注射的5倍。THP动脉注射在血液中的浓度和AUC值均小于静脉注射，在子宫组织的药物浓度和AUC值与静脉注射没有差别，但在心、肺组织的含量只有静脉注射的1／2；在盆腔淋巴及周围组织中，动脉注射THP的浓度是静脉注射的5倍；动静脉注射THP的血液组织的分配比率均达上百倍。结论：持续动脉注射5-Fu和THP较静脉持续注射表现不同程度的优势，这种优势与药物的药理特性有关。

Objective： To study the pharmacokinetics and factors influencing consecutive internal iliac arterial and intravenous infusion of 5-fluorouracil 5-FU and 4＇ -O-tetrahydropyranyladriamycin （THP） and provide the experimental evidence to optimize intraartery chemotherapy for pelvic malignant tumor. Methods：Mature female New Zealand rabbits were divided randomly into two groups. One group was consecutively infused by 5-FU and THP via internal iliac artery for 6 h. The other group was consecutively infused by 5- FU and THP via ear vein. The blood samples and the uterus tissue specimens were collected at various time points during the infusion period. At the end of infusion, the rabbits were sacrificed via intravenous air embolism and the heart, lung, and the node-rich pelvic adipose tissues were collected. The drug concentrations in plasma and tissue specimens were determined by high performance liquid chromatography methods. Results：The peak plasma concentration and AUC （area under curve） of intra-arterial infusion of 5-FU were a little lower than those via intravenous infusion. The peak concentration of intra-arterial infusion of 5-FU were 2-3 fold increased in uterus tissues and 5-fold increased in pelvic lymph node and adjacent tissues compared with those via intravenous infusion. The peak plasma concentration and AUC of intra-arterial infusion of THP were lower than those via intravenous infusion. The peak concentration and AUC of intra-arterial infusion of THP were not significantly different in uterus tissues between the two infusion forms. The peak concentration of THP was decreased by 50% in heart and lung tissues but increased to 5-fold in pelvic peripheral lymph node tissues by intra-arterial infusion than those by intravenous infusion. The serum to tissue vein distribution ratio of THP was several hundred times. Conclusions： Consecutive intra-arterial infusion of 5-FU and THP had some advantages compared with continuous intravenous infusion at different degrees. These advantages depended on the drugs＇pharmacological properties.