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標題: | 探討核苷轉運蛋白ENT1在治療亨丁頓舞蹈症的腺苷衍生物之藥物動力學性質中所扮演的角色 The role of ENT1 in pharmacokinetics of nucleoside analogues for the treatment of Huntington's disease. |
作者: | Hui-Ting Yang 楊惠婷 |
指導教授: | 林君榮 |
關鍵字: | 亨丁頓舞蹈症,ENT1,藥物動力學性質,化合物-A,化合物-B,腺?, ENT1,pharmacokinetics,compound-A,compound-B,adenosine, |
出版年 : | 2015 |
學位: | 碩士 |
摘要: | 亨丁頓舞蹈症 (Huntington’s disease; HD) 為遺傳性的神經退化疾病 (neurodegenerative disease),隨著病程的演進,病人伴隨有舞蹈症 (Chorea)、精神失常 (psychiatric manifestations)、認知障礙 (cognitive loss) 等症狀。本研究的目的在探討 ENT1對於腺苷 (adenosine) 的結構類似物 (化合物-A及化合物-B) 藥動學性質之影響。我們首先測量 mENT1 mRNA在R6/2 HD小鼠以及其wild-type (WT) 控制組各組織的表現量;接著利用mENT1 WT 及knock out (KO) 小鼠模型,觀察化合物在血液中的分布情形、靜脈給予小鼠化合物,評估化合物血中濃度時間曲線圖,同時萃取小鼠腦部瞭解化合物通過血腦屏障 (blood-brain barrier,BBB) 的通透情形以及腦部adenosine的濃度變化。
實驗結果顯示在R6/2 WT及HD小鼠組織中,mEnt1基因表現量不會受到疾病的影響。於血液中的分布情形而言,化合物-A的KB/P近似於1,化合物-B的KB/P > 1,這表示化合物-B會分布到紅血球中;尾靜脈注射化合物-A後,在mENT1 WT與KO小鼠血液中,化合物-A的AUC分別為19989±1904、28207±4252 ng×min/mL;注射化合物-B後,在mENT1 WT與KO小鼠血液中,化合物-B的AUC分別為25738±5946、47230±15223 ng×min/mL;化合物血液中至腦部組織的比例,化合物-A在WT與KO小鼠沒有顯著的差異,化合物-B在WT小鼠明顯高於KO小鼠,且化合物-B血液中至腦部組織的比例較化合物-A高。然而在腦部微透析實驗中則發現,腹腔注射化合物-A之後,化合物本身及 adenosine 在紋狀體內有上升的趨勢;腹腔注射化合物-B之後,紋狀體內化合物本身及腺苷 (adenosine) 並無變化的跡象。由以上實驗結果可以知道mENT1對於compound-B的藥動性質影響較大。化合物-A能增加腦中adenosine濃度,化合物-B卻不能,這個現象的意義需要將來進一步研究去釐清。 Huntington’s disease (HD) is a progressive neurodegenerative disease characterized by chorea and the decline in psychiatric and cognitive functions. The objective of the present study was to investigate the role of ENT1 on the pharmacokinetics of adenosine analogues (compound-B and compound-A). mRNA levels of mouse ENT1 (mEnt1) were analyzed in R6/2 HD transgenic mice and the wild-type (WT) controls. Also, pharmacokinetic properties, including blood to plasma ratios (KB/P), blood concentration versus time curves, brain to blood ratios, and ability of compounds to pass through the blood brain barrier (BBB), of these compounds were evaluated in mENT1 knock out (KO) mice and the wild-type (WT) controls. The results showed that the expression levels of mEnt1 were comparable between R6/2 WT and HD mice. The KB/P of compound-A is approximate to 1 and compound-B is greater than 1, suggesting that compound-B is distributed into red blood cells. For compound-B, the AUC values were 25738±5946、47230±15223 ng×min/mL in mENT1 WT and KO mice, respectively. For compound-A, the AUC values were 19989±1904、28207±4252 ng×min/mL in mENT1 WT and KO mice, respectively. From the data of brain and blood extraction, the brain to blood ratios of compound-A was no difference in WT and KO mince, compound-B was higher in WT mice than in KO mice, whereas this ratio was higher for compound-B than for compound-A. On the other hand, the results of in-vivo brain microdialysis study showed that the brain extracellular levels of compound-A and adenosine tended to increase after an intraperitoneal injection of 10 mg/kg of compound-A, whereas the concentration of compound-B and adenosine remained unchanged after the administration (i.p. 10 mg/kg of compound-B). These data suggest that the expression of mENT1 may have more profound effects on the pharmacokinetics of compound-B than on that of compound-A. However, since it is compound-A but not compound-B that increased brain extracellular levels of adenosine, further study is required to eludicate the pharmacodynamic impact of these findings. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51571 |
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顯示於系所單位: | 藥學系 |
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