治療亨丁頓舞蹈症的核苷衍生物之藥物動力學性質研究

Abstract

亨丁頓舞蹈症 (Huntington’s disease; HD) 為huntingtin基因上CAG三核酸重覆序列擴增所導致的神經退化性疾病，至今亨丁頓舞蹈症仍然無藥可治，因此許多研究致力於尋找標的物以改善症狀，近來更有研究指出藉由調控腺苷 (adenosine) 的系統或許是一個可行的策略。 化合物A是從天麻所萃取出來的腺苷衍生物，它本身具有抑制ENT1及活化A2A受體的雙重功效，除了化合物A之外，也經由結構修改合成了另外兩個腺苷衍生物化合物B及化合物C。有鑑於口服藥物之便利性，所以本研究以MDCK II細胞攝取實驗、原位小腸灌流試驗及生體可用率試驗去評估這三種化合物的口服吸收效果。在腦部分佈的部分，以ARBEC細胞攝取實驗去評估這三種化合物在血腦障壁 (blood-brain barrier; BBB) 的通透程度，更以ICR小鼠給予尾靜脈注射化合物後，測量其血液中至腦部組織的比例 (brain/blood ratio)，最後則是以Wistar大鼠腹腔注射化合物後，利用腦部微透析去分析紋狀體內化合物及腺苷的濃度。 預測之人類腸道吸收分率在化合物A、化合物B及化合物C分別為0.41 ± 0.12、0.77 ± 0.07、0.87 ± 0.01，而化合物於小鼠的生體可用率在化合物A、化合物B及化合物C分別為5.48 %、7.13 %、25.99 %。對於化合物腦部分佈而言，在ICR小鼠化合物C自血液中至腦部組織的比例會隨著時間而上升，其餘兩者則是下降，然而在Wistar大鼠腦部微透析實驗中則發現腹腔注射化合物C之後，紋狀體內化合物C及adenosine並無變化的跡象，反倒是腹腔注射化合物A及化合物B之後，化合物本身及adenosine在紋狀體內有上升的趨勢，關於化合物C在brain/blood ratio與微透析實驗結果之矛盾，推測是其組織結合力 (tissue binding) 太高所致。總而言之，藥物動力學性質研究顯示基於口服吸收性質而言化合物C最有潛力發展為口服藥物，但是其腦部分佈特性仍須進一步加以釐清。

Huntington’s disease (HD) is a neurodegenerative disease caused by the CAG trinucleotide expansion in the huntingtin gene. So far, there is no effective drug for HD treatment and many studies have been carried out to explore the therapeutic targets to alleviate the symptoms of HD. Recently, some studies indicated that modulating the adenosinergic system may be a feasible strategy. Compound A, an adenosine analogue extracted from Gastrodia elata (GE), has the dual function of ENT1 inhibition and A2A receptor activation. In addition to compound A, two adenosine analogues derived from compound A, compound B and compound C, were synthesized. Considering the fact that oral drug is convenient, in this study, MDCK II uptake study, in situ intestinal perfusion, and bioavailability (BA) study were performed to evaluate oral absorption of these compounds. For brain distribution, ARBEC uptake study was conducted to investigate the ability of these compounds to pass through the blood-brain barrier (BBB). Blood to brain ratios (brain/blood ratios) were measured in ICR mice given compounds by tail vein injection. Also, compounds were administrated to the Wistar rats by intraperitoneal injection and the concentrations of compounds and adenosine in striatum were detected by in-vivo brain microdialysis. The predicted fraction absorbed (Fa) in human of compound A, compound B and compound C were 0.41 ± 0.12, 0.77 ± 0.07 and 0.87 ± 0.01, respectively. The bioavailability (BA) values in mice were 5.48 %, 7.13 %, and 25.99 % for compound A, compound B and compound C, respectively. With regard to the distribution in the brain, the blood to brain ratio of compound C was increased over time in the ICR mice, whereas the blood to brain ratio was decreased over time in other two compounds. In the brain microdialysis study, the concentrations of compound C and adenosine are unchanged, but the concentrations of compound A, compound B and adenosine have the trend of increase after intraperitoneal injection of these compounds. The discrepancy between blood to brain ratio and microdialysis for compound C may attribute to its high tissue binding. In conclusion, the pharmacokinetic study suggests that compound C may have the potential to be developed as an oral drug with respect to oral absorption property, whereas its distribution in the brain need to be further elucidated.