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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 余秀瑛(Hsiu-Ying Yu),何藴芳(Yunn-Fang Ho) | |
dc.contributor.author | Da-Kong Huang | en |
dc.contributor.author | 黃大剛 | zh_TW |
dc.date.accessioned | 2021-06-13T17:27:34Z | - |
dc.date.available | 2005-01-28 | |
dc.date.copyright | 2005-01-28 | |
dc.date.issued | 2004 | |
dc.date.submitted | 2004-12-13 | |
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Biopharm Drug Dispos 1999; 20:241-7. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/39397 | - |
dc.description.abstract | 中文摘要
St. John’s wort(Hypericum perforatum,SJW)萃取物為目前普遍使用的保健食品之一,其廣泛地被使用於輕度到中度憂鬱症的治療。然而,近年來有許多人體臨床試驗及報告提到,服用SJW萃取物可能會產生一些不良的藥品交互作用,像是SJW會降低HIV蛋白酶抑制劑(HIV protease inhibitors,HIV PIs)indinavir在人體的血中濃度。因此,本研究欲建立一動物模式探討SJW與indinavir間之藥品交互作用。 經由調整移動相之pH值與乙腈(acetonitrile)所含之比例後,本研究也建立一高效能液相層析(high-performance liquid chromatography,HPLC)之分析方法,可同時測量大鼠中indinavir、saquinavir及ritonavir三種蛋白酶抑制劑之血中濃度。此HPLC之分析方法是以C18之逆相層析管柱進行分析,UV偵測波長為215 nm,且三種蛋白酶抑制劑的濃度線性範圍皆在100 ~ 10,000 ng/mL之間。 本研究動物模式之實驗結果可以明顯地觀察到SJW與indinavir間之藥品交互作用。每日口服投予150 mg或300 mg的SJW萃取物予雄性Wistar大鼠連續15天後,SJW能夠降低大鼠體中indinavir之血中濃度,並改變indinavir相關之藥品動態學參數。如:血中濃度對時間之曲線下面積(area under the concentration versus time curve,AUC)由5.20 | zh_TW |
dc.description.abstract | 英文摘要
St. John’s wort (Hypericum perforatum, SJW) is one of the most popular herbal preparations widely used in the treatment of mild to moderate depression. However, a series of case reports and clinical studies indicate SJW play a role in drug interactions. In some clinical observations, SJW can reduce the plasma concentration of indinavir, a HIV protease inhibitor. In our study, an animal model for the investigation of the herb-drug interactions between SJW and indinavir has been established. By optimizing pH value and acetonitrile content of the mobile phase, a modified high-performance liquid chromatographic (HPLC) method has also been developed for the simultaneously quantitative determination of three HIV protease inhibitors indinavir, saquinavir, and ritonavir in rat plasma. Chromatography was performed using a C18 reversed-phase column. Ultraviolet detection at 215 nm was used. Linearity of the method was obtained in the concentration range of 100-10000 ng/mL for all three HIV protease inhibitors. Herb-drug interactions between SJW and indinavir can be clearly observed in the Wistar rat model. Oral administration of either 150 mg/day or 300 mg/day SJW extracts for 15 days obviously reduced the plasma concentrations of indinavir and changed its certain pharmacokinetic parameters. The area under the curve (AUC) of indinavir decreased significantly from 5.20 | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T17:27:34Z (GMT). No. of bitstreams: 1 ntu-93-R90423013-1.pdf: 723776 bytes, checksum: 46c7052b208fd5bbe5002c2181132bd1 (MD5) Previous issue date: 2004 | en |
dc.description.tableofcontents | 總目錄
中文摘要………………………………………………Ⅰ 英文摘要………………………………………………Ⅱ 目錄……………………………………………………Ⅲ 圖目錄…………………………………………………Ⅳ 表目錄…………………………………………………Ⅴ 目錄 第一章 文獻探討 1 第一節 前言 1 第二節 人類免疫缺乏病毒(Human Immunodeficiency Virus) 3 一、Human Immunodeficiency Virus簡介 3 二、Human Immunodeficiency Virus蛋白酶 5 第三節 Human Immunodeficiency Virus蛋白酶抑制劑 6 一、Human Immunodeficiency Virus蛋白酶抑制劑的藥理作用 7 二、臨床上常見之Human Immunodeficiency Virus蛋白酶抑制劑 7 第四節 Indinavir之藥品動態學 13 一、Indinavir在大鼠之藥品動態學 13 二、Indinavir在其他動物及人體之藥品動態學 17 第五節 St. John’s wort 20 一、St. John’s wort及其內含成分 20 二、St. John’s Wort藥理作用簡介 23 三、St. John’s wort與Cytochrome P450及P-glycoprotein之關聯 25 第六節 St. John’s wort與Indinavir間藥品交互作用研究 27 第二章 實驗動機與目的 28 第三章 實驗試劑與儀器 29 第一節 實驗藥品與試劑 29 第二節 實驗儀器 30 第三節 實驗溶液的製備 31 一、0.5% Carboxymethyl cellulose sodium salt(CMC-Na)水溶液 31 二、1%磷酸水溶液 31 三、10%氨水 31 四、pH 4.8磷酸鹽緩衝溶液(pH 4.8 50 mM Na2HPO4 solution) 31 五、沖提液 32 第四章 實驗步驟與方法 33 第一節 Indinavir、Saquinavir與Ritonavir之HPLC定量方法建立 33 一、移動相pH值對Indinavir、Saquinavir與Ritonavir解析度之影響 33 二、移動相組成比例對Indinavir、Saquinavir與Ritonavir解析度之影響 33 三、以Gradient Elution方式分析Indinavir、Saquinavir與Ritonavir之血中濃度 34 第二節 Indinavir之HPLC分析方法 35 一、血漿檢品的前處理 35 二、HPLC分析條件 35 三、Propylparaben之安定性 36 第三節 分析方法之確效 38 一、同日間之精確度與準確度(Intraday Precision and Accuracy) 38 二、異日間之精確度與準確度(Interday Precision and Accuracy) 39 三、校正曲線(Calibration Curve) 39 四、絕對回收率(Absolute Recovery) 39 第四節 動物實驗 43 一、動物實驗操作 43 二、單獨投予Indinavir Sulfate 43 三、St. John’s wort與Indinavir間之藥品交互作用 44 第五節 藥品動態學之分析 45 第五章 實驗結果 46 第一節 Indinavir、Saquinavir與Ritonavir之HPLC分析方法建立 46 一、移動相pH值對Indinavir、Saquinavir與Ritonavir解析度之影響 46 二、移動相組成比例對Indinavir、Saquinavir與Ritonavir解析度之影響 49 三、以Gradient Elution方式分析Indinavir、Saquinavir與Ritonavir之血中濃度 52 四、Propylparaben之安定性 54 第二節 分析方法之確效 55 一、同日間之準確度與精密度 55 二、異日間之準確度與精密度 58 三、絕對回收率 61 第三節 Indinavir、Saquinavir與Ritonavir之分析方法 62 第四節 動物實驗 63 一、單獨口服投予Indinavir 63 二、St. John’s wort與Indinavir間之藥品交互作用 66 第六章 討論 67 第一節 Indinavir、Saquinavir與Ritonavir HPLC分析法之建立 67 一、本研究與其他研究使用之層析管柱差異 67 二、移動相pH值對Indinavir、Saquinavir與Ritonavir解析度之影響 69 三、移動相組成比例對Indinavir、Saquinavir與Ritonavir解析度之影響 70 第二節 動物實驗操作技巧 72 第三節 大鼠體中Indinavir之藥品動態學參數與相關文獻之探討 76 一、單獨投予indinavir之控制組 76 二、先投予St. John’s wort萃取物之實驗組 77 第四節 St. John’s wort與Indinavir間藥品交互作用機轉之探討 79 一、St. John’s wort與Indinavir間藥品交互作用發生機轉之推測 79 二、由Indinavir藥動學參數變化探討交互作用之可能機轉 80 三、St. John’s wort萃取物對Indinavir吸收或代謝影響之探討 82 四、St. John’s wort萃取物對P-glycoprotein與CYP3A影響之探討 83 五、St. John’s wort萃取物活性成分對CYP3A影響 84 第五節 臨床上之建議 84 第七章 結論 85 第八章 參考文獻 87 圖目錄 圖1. HIV基因表現後經蛋白質分解得到數種具有個別功能的蛋白質 4 圖2. HIV蛋白酶之結構 5 圖3. Indinavir sulfate之化學結構 8 圖4. Saquinavir之化學結構 9 圖5. Ritonavir之化學結構 10 圖6. Nelfinavir之化學結構 11 圖7. Amprenavir之化學結構 12 圖8. Lopinavir之化學結構 12 圖9. Indinavir可能之代謝方式 18 圖10. Indinavir在human S9 preparation中可能主要代謝產物 19 圖11. St. John’s wort內含主要成分之化學結構 22 圖12. 人體臨床試驗中,連續服用St. John’s wort對indinavir血中濃度之影響27 圖13. 檢品分析時,移動相乙腈的體積百分比變化對時間圖 34 圖14. Propylparaben之化學結構 37 圖15. 計算絕對回收率之標準品溶液配製流程圖 41 圖16. 計算絕對回收率之血漿檢品萃取步驟流程圖 42 圖17. 移動相pH值對indinavir、saquinavir與ritonavir解析度影響 47 圖18. 移動相pH值對indinavir、saquinavir與ritonavir解析度影響 48 圖19. 移動相之乙腈含量百分比對indinavir、saquinavir與ritonavir解析度影響 50 圖20. 移動相之乙腈含量百分比對indinavir、saquinavir與ritonavir解析度影響 51 圖21. 大鼠體中indinavir血中濃度之層析圖 53 圖22. Popylparaben之水解反應式 54 圖23. Indinavir同日間之校正曲線 55 圖24. Saquinavir同日間之校正曲線 56 圖25. Ritonavir同日間之校正曲線 57 圖26. Indinavir異日間之校正曲線 58 圖27. Saquinavir異日間之校正曲線 59 圖28. Ritonavir異日間之校正曲線 60 圖29. 先以150 mg/day或300 mg/day的St. John’s wort萃取物口服投予大鼠連續15天後,St. John’s wort萃取物對indinavir血中濃度之影響 65 圖30. 口服投予大鼠藥物之實驗操作圖 73 表目錄 表1. 常見HIV蛋白酶抑制劑之物化性質比較…………………………………..…7 表2. 口服投予HIV蛋白酶抑制劑之動物實驗設計比較…………………………15 表3. 各大鼠相關研究中,indinavir藥品動態學參數比較……………………….16 表4. 不同緩衝溶液之pH值對HIV蛋白酶抑制劑解析度之影響……………….48 表5. 移動相比例對HIV蛋白酶抑制劑解析度之影響……………………………51 表6. Indinavir同日間之精密度……………………………………………………..55 表7. Saquinavir同日間之精密度……………………………………………………56 表8. Ritonavir同日間之精密度……………………………………………………..57 表9. Indinavir異日間之精密度……………………………………………………..58 表10. Saquinavir異日間之精密度…………………………………………………..59 表11. Ritonavir異日間之精密度…………………………………………………....60 表12. 三種HIV蛋白酶抑制劑之絕對回收率…………………………………..…61 表13. 先以150 mg/day或300 mg/day的St. John’s wort萃取物口服投予大鼠連續15天後,St. John’s wort萃取物對indinavir之藥品動態學參數影響…….64 表14. 使用於分析HIV蛋白酶抑制劑之HPLC層析管柱特性比較…………..…68 表15. HIV蛋白酶抑制劑之HPLC分析條件比較…………………………………71 | |
dc.language.iso | zh-TW | |
dc.title | 三種蛋白酶抑制劑血中濃度測定法之建立及St. John's wort對Indinavir在大鼠體內之藥動學交互作用探討 | zh_TW |
dc.title | Simultaneous Determination of Three HIV Protease Inhibitors in Plasma and Drug Interactions between St. John's wort and Indinavir in Rats | en |
dc.type | Thesis | |
dc.date.schoolyear | 93-1 | |
dc.description.degree | 碩士 | |
dc.contributor.advisor-orcid | ,何藴芳(yfho@ntu.edu.tw) | |
dc.contributor.oralexamcommittee | 蔡東湖,李水盛 | |
dc.subject.keyword | 蛋白酶,抑制劑, | zh_TW |
dc.subject.keyword | HIV protease inhibitors, | en |
dc.relation.page | 92 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2004-12-14 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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