基于脑微透析技术的大鼠中枢左旋多巴药动学研究及帕金森病大鼠模型的建立

发布时间：2018-05-14 01:37

本文选题：左旋多巴 + 脑微透析　；参考：《福建医科大学》2011年硕士论文

【摘要】：目的 1.探讨美多芭片(左旋多巴(Levodopa,LD)+苄丝肼(Benserazide,BZE))中LD在大鼠外周血及纹状体细胞外液中的药动学行为及其相关性; 2.建立帕金森病(Parkinson’s Disease,PD)大鼠模型,并对其进行评价。方法 1. SD大鼠分两组,分别按照LD 42 mg?kg-1和LD 80 mg?kg-1灌胃给予美多芭,利用脑微透析技术收集大鼠纹状体细胞外液透析液,同时采集大鼠外周血;高效液相色谱-电化学(HPLC-ECD)法测定透析液及外周血中LD浓度;应用3p97软件及NONMEM软件进行数据处理,估算药动学参数,并用NONMEM软件建立LD药动学模型。 2. 6-羟多巴胺(6-HydroxyDopamine,6-OHDA)单侧两点损毁建立大鼠PD模型:利用脑立体定位仪在大鼠单侧前脑内侧束(Medial Forebrain Bundle, MFB)及黑质(Substantia Nigra pars compacta,SNc)注射6-OHDA溶液(12μg·4μL-1),两周后,腹腔注射阿扑吗啡(1mg·kg-1),判定建模是否成功。结果 1. LD在大鼠纹状体细胞外液及外周血中的药动学行为存在差异。与外周血比较,纹状体细胞外液达峰时间( tmax)延长,达峰浓度(Cmax)及药时曲线下面积(AUC)显著减小,但LD通过血脑屏障进入中枢的比值相对固定(3%左右),纹状体细胞外液t1/2与外周血无明显差异,纹状体细胞外液中LD浓度(特别在消除相)与外周血LD浓度存在相关性。NONMEM软件分析表明给药剂量对大鼠LD药动学参数无影响,体重影响大鼠LD药动学参数K32,但对其它参数无影响。 2.建立了PD大鼠模型,成功率为27.5%。结论 1.通过脑微透析技术采集大鼠纹状体细胞外液透析液并利用HPLC法测定LD浓度,适用于大鼠纹状体细胞外液LD药动学研究。 2. NONMEM法建立的大鼠药动学模型具有较好的稳定性、内部有效性及预测能力,能较好地描述LD在大鼠中枢及外周血中的药动学特点。 3.应用6-OHDA单侧两点损毁技术可成功建立大鼠PD模型。
[Abstract]:Purpose 1. To investigate the pharmacokinetic behavior of LD in the peripheral blood and striatum extracellular fluid of rats in Levodopaus LDD (Benserazide BZEEN). 2. A rat model of Parkinson's disease (PD) was established and evaluated. Method 1. Sprague-Dawley rats were divided into two groups. According to LD 42 mg?kg-1 and LD 80 mg?kg-1, medoba was administered intragastrically. The extracellular dialysate of striatum was collected by cerebral microdialysis and peripheral blood was collected at the same time. The LD concentration in dialysate and peripheral blood was determined by high performance liquid chromatography-electrochemical HPLC-ECD, the data were processed by 3p97 software and NONMEM software, the pharmacokinetic parameters were estimated, and the LD pharmacokinetic model was established by NONMEM software. 2. Rat PD model was established by 6-hydroxydopamine 6-hydroxyDopamine6-OHDA-unilateral two-point lesion. Medial Forebrain Bundle, MFB) and substantia nigra Nigra pars compactathione were injected into the unilateral medial forebrain Forebrain Bundle, MFB) and substantia nigra Nigra pars, respectively. After two weeks, the rats were injected intraperitoneally with 1 mg / kg of apomorphine to determine whether the model was successful. Result 1. The pharmacokinetic behavior of LD in extracellular fluid and peripheral blood of rat striatum was different. Compared with peripheral blood, striatum extracellular fluid peak time (tmaxmax) was prolonged, peak concentration (C max) and area under the drug time curve (AUC) decreased significantly. However, the ratio of LD entering the center through the blood-brain barrier was about 3%, and there was no significant difference between the striatum extracellular fluid t1 / 2 and the peripheral blood. There was a correlation between LD concentration in striatum extracellular fluid (especially in elimination phase) and LD concentration in peripheral blood. The analysis of NONMEM software showed that the dose of drug had no effect on the pharmacokinetic parameters of LD in rats. Body weight affected LD pharmacokinetic parameters K 32, but had no effect on other parameters. 2. The rat model of PD was established, and the success rate was 27.5%. Conclusion 1. The extracellular dialysate of rat striatum was collected by microdialysis technique and the LD concentration was measured by HPLC method, which is suitable for the pharmacokinetic study of rat striatum extracellular fluid LD. 2. The rat pharmacokinetic model established by NONMEM method has good stability, internal validity and predictive ability, and can well describe the pharmacokinetic characteristics of LD in central and peripheral blood of rats. 3. The PD model of rats can be successfully established by using the technique of unilateral two-point lesion of 6-OHDA.
【学位授予单位】：福建医科大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R969.1;R-332

【参考文献】