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背景:5-氟尿嘧啶(5-Fluorouracil,5-Fu)是最常用的消化道肿瘤化疗药物之一,但是其副作用却限制了它进一步临床应用。目的:5-Fu原药及其壳聚糖(chitosan,CS)-聚天冬氨酸(polyaspartic acid,Pasp)纳米粒子小鼠灌胃后血药浓度曲线及其药代动力学初步研究,了解5-Fu经纳米包载后是否具有缓释作用。设计、时间及地点:随机对照动物实验,于2006-10/2007-06在中山医院消化科实验室完成。材料:健康雌性昆明小鼠180只由复旦大学动物实验中心提供。5-Fu(纯度99%)由上海旭东海普药业有限公司提供。2种CS-Pasp-5Fu纳米粒子由复旦大学高分子科学系聚合物工程教育部重点实验室制备。方法:同性健康昆明小鼠分为3组,分别予5-Fu原药及其2种CS-Pasp-5Fu纳米粒子灌胃,灌胃后15min,1,2,4,6,8,12,16,24和48h10个时间点取血,高效液相色谱法测其血药浓度,代入3P97程序计算各样品的药代动力学参数并作比较。主要观察指标:相对回收率,绝对回收率,样品稳定率。结果:5-FU原药组的药物峰浓度出现在灌胃后15min之内,此后血药浓度迅速降低。CS-Pasp-5Fu纳米粒子1组的药物峰浓度出现在灌胃后6h左右,并在14h内维持较高的浓度。CS-Pasp-5Fu纳米粒子2组的血药浓度曲线呈双峰形,药物峰浓度分别出现在灌胃后2h和16h左右,24h后下降。与5-Fu原药相比,2种CS-Pasp-5Fu纳米粒子的血药峰浓度(Cmax)降低,半衰期(T1/2)延长,血药浓度时间曲线下面积明显增加。结论:CS-Pasp-5FU纳米粒子具有缓释作用。
BACKGROUND: 5-Fluorouracil (5-Fu) is one of the most commonly used chemotherapeutic drugs for gastrointestinal tumors, but its side effects have limited its further clinical application. OBJECTIVE: To study the plasma concentrations of 5-Fu and its chitosan (CS) -polyaspartic acid (Pasp) nanoparticles after gavage, and to understand the pharmacokinetics 5-Fu after nano-encapsulated whether it has a sustained release effect. DESIGN, TIME AND SETTING: A randomized controlled animal experiment was performed at the Laboratory of Gastroenterology, Zhongshan Hospital from October 2006 to June 2007. MATERIALS: 180 healthy female Kunming mice were provided by Fudan University Animal Experimental Center. 5-Fu (purity 99%) provided by Shanghai Xu Dong Haipu Pharmaceutical Co., Ltd. Two CS-Pasp-5Fu nanoparticles were prepared by the Key Laboratory of Polymer Engineering, Ministry of Education, Department of Polymer Science, Fudan University. Methods: Homosexual Kunming mice were divided into 3 groups: 5-Fu and 2 CS-Pasp-5Fu nanoparticles were intragastrically administrated at 15 min, 1, 2, 4, 6, 8, 16, 24 and 48h 10 time points to take blood, high performance liquid chromatography measured plasma concentration, substituted into the 3P97 program to calculate the pharmacokinetic parameters of each sample and compared. MAIN OUTCOME MEASURES: Relative recovery, absolute recovery, sample stability. Results: The peak drug concentration in 5-FU drug group appeared within 15min after intragastric administration, and the plasma concentration decreased rapidly thereafter. The drug peak concentration of CS-Pasp-5Fu nanoparticle 1 group appeared about 6h after gavage, and maintained a higher concentration within 14h. The plasma concentration curve of CS-Pasp-5Fu nanoparticles showed a bimodal pattern. The drug peak concentrations appeared at 2h and 16h after gavage, respectively, and decreased after 24h. Compared with 5-Fu original drug, the two CS-Pasp-5Fu nanoparticles had lower peak plasma concentration (Cmax), longer half-life (T1 / 2) and significantly increased area under the plasma concentration time curve. Conclusion: CS-Pasp-5FU nanoparticles have a sustained release effect.