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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 蘇南維(Nan-Wei Su) | |
| dc.contributor.author | Jou-An Chen | en |
| dc.contributor.author | 陳柔安 | zh_TW |
| dc.date.accessioned | 2021-07-10T21:39:01Z | - |
| dc.date.available | 2021-07-10T21:39:01Z | - |
| dc.date.copyright | 2020-08-24 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-08-14 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/76868 | - |
| dc.description.abstract | 橙皮素 (hesperetin, Hst) 為類黃酮化合物，廣泛存在於柑橘屬果實之植物次級代謝物，具有預防心血管疾病、提升免疫力、抗癌症等生理活性。然而Hst的水溶性不佳，生物可利用率 (bioavaiability) 極低，使其在食品與藥品應用上受到許多限制。本研究室先前篩選出Bacillus subtilis BCRC 80517菌株中具有類黃酮磷酸酯合成酶 (flavonoid phosphate synthetase) 可將類黃酮磷酸酯化形成橙皮素磷酸酯衍生物 (hesperetin phosphate derivatives, HstPs)，hesperetin 7-O-phosphate (Hst7P) 與hesperetin 3'-O-phosphate (Hst3'P) 。在製藥工業上常利用磷酸化手段合成磷酸酯前驅藥物 (phosphate ester prodrug) 進而提升生物可利用率。本研究的主要目的在於利用Caco-2 細胞與藥物動力學試驗評估HstPs之生物可利用率並和Hst及市售橙皮素衍生物產品如橙皮苷 (hesperidin, Hsd) 與葡糖基橙皮苷 (α glucosyl hesperidin, G-Hsd) 比較。HstPs與Hst的基本物化性質如溶解度與安定性的結果顯示Hst7P 和Hst3'P於橙皮素之相對溶解度分別為 1446與1544倍；HstPs與Hst在240分鐘模擬胃液 (simulated gastric fluid, SGF) 與模擬腸液 (simulated intestinal fluid, SIF) 反應下的安定性良好，顯示橙皮素磷酸酯可以原始型態順利達腸道被吸收。在HBSS緩衝溶液之穿透試驗，比較50 μM Hst7P、Hst3'P、Hst、Hsd與G-Hsd 五者之穿透比率與表觀穿透係數 (Apparent permeability coefficient, Papp )，結果顯示Hst7P與Hst3'P的Papp各為9.27×10−6 與10.67×10−6 (cm/sec)，遠高於Hst (4.87×10−6cm/sec)、Hsd (0.12×10−6cm/sec) 與G-Hsd (0.22×10−6cm/sec)，顯示化合物溶解程度與分子大小影響穿透程度。此外本研究比較Caco-2 細胞鹼性磷酸酶 (alkaline phosphatase, ALP) 對 fosphenytoin (phosphate ester prodrug之控制組) 和HstPs之水解效率，結果顯示與fosphenytoin 相比ALP對HstPs有較佳的水解效率。最後由藥物動力學體內試驗的結果顯示HstPs可大幅增加口服後血漿內Hst濃度，吸收率較佳。綜合而論，HstPs如Hst7P 和Hst3'P相較Hst及市售產品如Hsd與G-Hsd具有較高的生物可利用率，未來在保健食品應用上深具潛力，可作為目前市售產品的有利競爭者。 | zh_TW |
| dc.description.abstract | Hesperetin (Hst) is one of the secondary metabolite in citurs fruit, which has a number of pharmacological and biological activities, such as ameliorating cardiac inflammation, increasing intact immunity systems, activities of anti-cancer; however, the application of Hst has been restricted because of low water solubility and poor bioavailability. Our previous study had revealed two phosphorylated hesperetin (HstPs), e.g. hesperetin 7-O-phosphate (Hst7P) and hesperetin 3'-O-phosphate (Hst3'P), derived by Bacillus subtilis BCRC 80517 bioconversion with Hst. On the basis of phosphate prodrug, Hst7P and Hst3'P were supposed to be absorbed more effective in intestinal in contrast to Hst. This study was aimed to explore the bioavailability of HstPs, Hst and its derivatives, including hesperidin (Hsd) and alpha glucosyl hesperidin (G-Hsd), through in vitro Caco-2 cells monolayer assay and in vivo pharmacokinetic study. First, we revealed that HstPs displayed 1446 and 1544 times higher in aqueous solubility than Hst. In addition, either HstPs or Hst were stable in both simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) during 240-min incubation. In in vitro transport study, HstPs exhibited higher permeation rate and apparent permeability rate (Papp). The results showed that the Papp values of Hst7P and Hst3’P were 9.27×10−6 and 10.67× 10−6 (×10-6cm/sec), respectively, higher than Hst (4.87×10−6cm/sec), Hsd (0.12×10−6cm/sec), and G-Hsd (0.22×10−6cm/sec), indicated that HstPs enhanced in vitro intestinal permeability of Hst and its derivatives. The results’ of dephosphorylation assay indicated the compounds could be hydrolyzed effectively by the membrane-associated alkaline phosphatase (ALP). In addition, the clearance half-life (T1/2) of Hst7P and Hst3'P were significantly lower than fosphenytoin. Moreover, HstPs greatly increased plasma exposure to Hst after oral administration in rats. Based on the phosphate prodrug concept, HstPs could be absorbed more effective and faster. Our finding indicated that HstPs have higher bioavailability than Hst, Hsd, and G-Hsd. | en |
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| dc.description.tableofcontents | 致謝 I 中文摘要 III ABSTRACT V 縮寫對照表 VII 目錄 IX 圖目錄 XII 表目錄 XIII 第一章、前言 1 第二章、文獻整理 2 一、類黃酮 2 1.1. 類黃酮簡介 2 1.2. 類黃酮生理活性 2 1.3. 類黃酮之生物與酵素轉換 5 二、口服藥物與生物可利用率 10 2.1. BCS分類系統 10 2.2. 小分子藥物吸收模式 11 2.3. 藥物吸收常見生理屏障 12 2.4. Hesperetin 於人體之口服生物可利用率 12 三、前驅藥物 22 3.1. 前驅藥物定義與介紹 22 3.2. 磷酸酯前驅藥物 22 四、Caco-2細胞與穿透試驗 30 第三章、材料與方法 31 一、實驗架構 32 二、實驗材料與儀器設備 33 2.1. 實驗材料 33 2.2. 化學藥品與試劑 34 2.3. 實驗儀器設備 34 三、分析條件建立 35 3.1. HPLC層析條件建立 35 3.2. UPLC-MS/MS層析條件建立 39 3.3. 減量線製備與定量作業 39 四、實驗方法 41 4.1. 各種溶液與試劑配製方式 41 4.2. 溶解度試驗 43 4.3. 安定性試驗 43 4.4. Caco-2細胞試驗 44 4.5. 動物試驗 49 4.6. 統計分析 49 第四章、結果與討論 51 一、HstPs 和hesperetin及其衍生物之基本物化性質比較 51 1.1. 溶解度試驗 51 1.2. 安定性試驗 51 二、Caco-2細胞模型建立 54 2.1. Caco-2細胞單層膜完整性測試 54 2.2. Caco-2細胞單層膜之SEM拍攝 54 三、Caco-2細胞體外試驗 57 3.1. HstPs、hesperetin、hesperidin與α glucosyl hesperidin之穿透試驗 57 3.2. HstPs之去磷酸化能力評估 62 3.3. 小結 65 四、動物體內試驗 66 4.1. HstPs、hesperetin、hesperidin與α glucosyl hesperidin之藥物動力學試驗 66 4.2. 小結 68 第五章、結論 69 第六章、參考文獻 71 圖目錄 圖2-1、類黃酮之共通分子結構 7 圖2- 2、六種主要的類黃酮化合物 8 圖2-3、BCS藥物分類系統 15 圖2-4、口服藥物經膜運輸之五種途徑 17 圖2-5、小腸表皮細胞構造 18 圖2-6、Hesperidin經由腸道微生物代謝之產物 19 圖2-7、Hesperidin與hesperetin 在小腸表皮細胞的吸收方式 20 圖2-8、Hesperidin與hesperetin 在人體代謝方式 21 圖2-9、前驅藥物概念圖示 27 圖2-10、磷酸酯衍生化前趨藥物經人類小腸鹼性磷酸酶作用後吸收機制 28 圖2-11、ALP水解fosphenytoin之機制 29 圖2-12、穿透試驗示意圖 31 圖4-1、HstPs和hesperetin在(A)模擬腸液與(B)模擬胃液中化合物安定性 53 圖4-2、Caco-2細胞單層膜之Scanning electron microsocpy (SEM)拍攝 56 圖4-3、HstPs、hesperetin、hesperidin與α glucosyl hesperidin之穿透率比較 58 圖4-4、Caco-2細胞鹼性磷酸酶對HstPs與fosphenytoin之降解情形 64 圖4-5、Hst7P、hesperetin、hesperidin與α glucosyl hesperidin之藥物動力學曲線圖 67 表目錄 表2-1、Hesperetin及其衍生物之化學結構 9 表2-2、各類黃酮 subclass 及其代表性化合物之溶解度及 BCS 分類 16 表2-3、藥物吸收屏障與相關設計之前驅藥物研究比 24 表2-4、磷酸酯前驅藥物成功前例 25 表3-1、各試驗化合物之外標準曲線 40 表4-1、HstPs、hesperetin、hesperidin 和α glucosyl hesperidin之水溶解度 52 表4-2、HBSS緩衝溶液中atenolol和metoprolol之表觀穿透係數 55 表4-3、HstPs、hesperetin、hesperidin與α glucosyl hesperidin穿透試驗之各層分佈 59 表4-4、HstPs、hesperetin、hesperidin與α glucosyl hesperidin之穿透率與表觀穿透係數 61 表4-5、HstPs與fosphenytoin於Caco-2細胞中鹼性磷酸酶酵素清除率比較 63 | |
| dc.language.iso | zh-TW | |
| dc.subject | 藥物動力學 | zh_TW |
| dc.subject | 橙皮素 | zh_TW |
| dc.subject | 橙皮素磷酸酯 | zh_TW |
| dc.subject | 磷酸化 | zh_TW |
| dc.subject | Caco-2細胞 | zh_TW |
| dc.subject | 前驅藥物 | zh_TW |
| dc.subject | hesperetin | en |
| dc.subject | pharmacokinetic study | en |
| dc.subject | prodrug | en |
| dc.subject | hesperetin phosphate conjugate | en |
| dc.subject | Caco-2 cell | en |
| dc.subject | phosphorylation | en |
| dc.title | 橙皮素磷酸酯衍生物生物可利用率之研究 | zh_TW |
| dc.title | Study on the bioavailability of hesperetin phosphate derivatives | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 李敏雄(Min-Syong Li),周志輝(Jhih-Huei Jhou),陳與國(Yu-Guo Chen),賴盈璋(Ying-Jhang Lai) | |
| dc.subject.keyword | 橙皮素,橙皮素磷酸酯,磷酸化,Caco-2細胞,前驅藥物,藥物動力學, | zh_TW |
| dc.subject.keyword | hesperetin,hesperetin phosphate conjugate,phosphorylation,Caco-2 cell,prodrug,pharmacokinetic study, | en |
| dc.relation.page | 76 | |
| dc.identifier.doi | 10.6342/NTU202003138 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2020-08-17 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科技學系 | zh_TW |
| 顯示於系所單位： | 生化科技學系 | |
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