本文選題：左旋多巴 + 腦微透析　； 參考：《福建醫(yī)科大學(xué)》2011年碩士論文

【摘要】：目的 1.探討美多芭片(左旋多巴(Levodopa,LD)+芐絲肼(Benserazide,BZE))中LD在大鼠外周血及紋狀體細(xì)胞外液中的藥動(dòng)學(xué)行為及其相關(guān)性; 2.建立帕金森病(Parkinson’s Disease,PD)大鼠模型,并對(duì)其進(jìn)行評(píng)價(jià)。 方法 1. SD大鼠分兩組,分別按照LD 42 mg?kg-1和LD 80 mg?kg-1灌胃給予美多芭,利用腦微透析技術(shù)收集大鼠紋狀體細(xì)胞外液透析液,同時(shí)采集大鼠外周血;高效液相色譜-電化學(xué)(HPLC-ECD)法測(cè)定透析液及外周血中LD濃度;應(yīng)用3p97軟件及NONMEM軟件進(jìn)行數(shù)據(jù)處理,估算藥動(dòng)學(xué)參數(shù),并用NONMEM軟件建立LD藥動(dòng)學(xué)模型。 2. 6-羥多巴胺(6-HydroxyDopamine,6-OHDA)單側(cè)兩點(diǎn)損毀建立大鼠PD模型:利用腦立體定位儀在大鼠單側(cè)前腦內(nèi)側(cè)束(Medial Forebrain Bundle, MFB)及黑質(zhì)(Substantia Nigra pars compacta,SNc)注射6-OHDA溶液(12μg·4μL-1),兩周后,腹腔注射阿撲嗎啡(1mg·kg-1),判定建模是否成功。 結(jié)果 1. LD在大鼠紋狀體細(xì)胞外液及外周血中的藥動(dòng)學(xué)行為存在差異。與外周血比較,紋狀體細(xì)胞外液達(dá)峰時(shí)間( tmax)延長,達(dá)峰濃度(Cmax)及藥時(shí)曲線下面積(AUC)顯著減小,但LD通過血腦屏障進(jìn)入中樞的比值相對(duì)固定(3%左右),紋狀體細(xì)胞外液t1/2與外周血無明顯差異,紋狀體細(xì)胞外液中LD濃度(特別在消除相)與外周血LD濃度存在相關(guān)性。NONMEM軟件分析表明給藥劑量對(duì)大鼠LD藥動(dòng)學(xué)參數(shù)無影響,體重影響大鼠LD藥動(dòng)學(xué)參數(shù)K32,但對(duì)其它參數(shù)無影響。 2.建立了PD大鼠模型,成功率為27.5%。 結(jié)論 1.通過腦微透析技術(shù)采集大鼠紋狀體細(xì)胞外液透析液并利用HPLC法測(cè)定LD濃度,適用于大鼠紋狀體細(xì)胞外液LD藥動(dòng)學(xué)研究。 2. NONMEM法建立的大鼠藥動(dòng)學(xué)模型具有較好的穩(wěn)定性、內(nèi)部有效性及預(yù)測(cè)能力,能較好地描述LD在大鼠中樞及外周血中的藥動(dòng)學(xué)特點(diǎn)。 3.應(yīng)用6-OHDA單側(cè)兩點(diǎn)損毀技術(shù)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.
【學(xué)位授予單位】：福建醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2011
【分類號(hào)】：R969.1;R-332

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