臺灣博碩士論文加值系統

近年來，St. John’s wort（Hypericum perforatum，SJW）萃取物普遍地被使用於輕度到中度憂鬱症的治療，其主要的活性成份包括hypericin、pseudohypericin及hyperforin等。研究報告顯示，SJW萃取物可能影響P-glycoprotein（Pgp）及Cytochrome P450（CYPs）於大鼠及人體中的活性，進而影響同為CYP3A4 和Pgp受質的HIV蛋白酶抑制劑indinavir之臨床效用。臨床試驗指出，服用SJW會降低indinavir在人體的血中濃度。因此，本研究期望建立一大鼠小腸灌流實驗模式，進一步釐清St. John’s wort與indinavir間之藥品交互作用。
由本實驗之結果可明顯地觀察到，每日餵食雄性Wistar大鼠300 mg的St. John’s wort萃取物連續15天後，在0.05、0.1、0.5及1 mL/min四種不同灌流速度時，小腸中水份的吸收率、水份的淨損量、indinavir的吸收率及indinavir吸收廓清率大部份都明顯降低；而indinavir於肝門靜脈及肝靜脈的血中濃度也明顯降低；大部份的藥品動態學參數亦明顯改變，其差異都具有統計上意義。但是，indinavir的肝臟萃取率及肝臟清除率的差異則不具有統計上意義。
由本實驗之結果推論，St. John’s wort與indinavir間之藥品交互作用中，Pgp及CYPs可能是很重要的影響因子。未來若能進一步研究大鼠小腸或肝臟中CYPs 及Pgp的活性及蛋白質量表現，將有助於釐清本實驗之藥品交互作用的原因。

In recent years, St. John''s wort (Hypericum perforatum, SJW) was used as an alternative therapy for the treatment of mild to moderate depression. Several active compounds from SJW have been isolated, including hypericin, pseudohypericin and hyperforin, etc. Besides, SJW may affect the activities of P-glycoprotein (Pgp) and cytochrome P450 (CYPs) in rats and human. In some clinical observations, SJW can reduce the plasma concentrations of indinavir, a HIV protease inhibitor, which is a substrate of CYP3A4 and Pgp. Therefore, a rat small intestine perfusion model was established for the investigation of the drug interactions between SJW and indinavir.
In our study, oral administration of 300 mg/day SJW extracts to male Wistar rats for 15 days mostly reduced the water absorption ratio, water net flux, indinavir absorption ratio and indinavir absorption clearance even using four different perfusion flow rates, 0.05, 0.1, 0.5 and 1 mL/min. Besides, the plasma concentrations of indinavir in portal vein and hepatic vein were reduced significantly, and certain pharmacokinetic parameters of indinavir were also changed. However, no significant difference was observed for the mean hepatic extraction ratio (EH) and hepatic clearance (CLH) after SJW pretreatment.
It is suggested that the activities of Pgp and CYPs might be involved in the drug interactions between SJW and indinavir. In the further study, the activity and protein expression of CYPs and Pgp in liver or small intestine will be clarified for the investigation of the drug interactions.

第一章 前言 ………………………………………………………… 1
第二章 文獻探討 …………………………………………………… 3
第一節 St. John’s wort …………………………………………………… 3
一、St. John’s wort之簡介 ………………………………………… 3
二、St. John’s wort其內含成分 …………………………………… 4
三、St. John’s wort其藥理作用及相關研究報告 ………………… 7
四、St. John’s wort對P-glycoprotein與Cytochrome P450
表現之影響 ………………………………………………… 11
第二節 人類免疫缺乏病毒（Human Immunodeficiency Virus，HIV）… 13
一、HIV之結構 ………………………………………………… 13
二、HIV之生命周期 …………………………………………… 14
三、HIV蛋白酶 ………………………………………………… 15
第三節 HIV蛋白酶抑制劑 …………………………………………… 16
一、HIV蛋白酶抑制劑Indinavir及Indinavir Sulfate之介紹…… 16
二、Indinavir在動物體內之藥品動態學 ………………………… 17
三、Indinavir在人體之藥品動態學 ……………………………… 19
四、St. John’s wort與Indinavir間之藥品交互作用……………… 21
第四節 小腸的生理學 ………………………………………………… 22
一、小腸之長度…………………………………………………… 22
二、小腸之運動…………………………………………………… 23
三、小腸之吸收…………………………………………………… 23
第五節大鼠小腸灌流實驗之簡介 …………………………………… 29
第三章 實驗動機與目的 …………………………………………… 31

第四章 實驗試劑與儀器 …………………………………………… 32
第一節 實驗藥品與試劑 ……………………………………………… 32
第二節 實驗儀器 ……………………………………………………… 33
第三節 實驗溶液的製備 ……………………………………………… 34
第五章 實驗步驟與方法 …………………………………………… 37
第一節 檢品之定量方法 ……………………………………………… 37
一、 HPLC系統及分析indinavir之條件 ………………………… 37
二、 Spectrophotometry及分析菊糖之條件 …………………… 37
第二節 小腸灌流之分析方法 ………………………………………… 39
一、實驗之分組方法 …………………………………………… 39
二、實驗流程 ……………………………………………………… 41
三、Indinavir的定量分析 ………………………………………… 46
四、菊糖的定量分析 …………………………………………… 47
五、小腸灌流實驗的數據分析…………………………………… 48
第三節 分析方法之確效 ……………………………………………… 51
一、菊糖之確效 ………………………………………………… 51
(1) 同日內之精確度與準確度 ………………………………… 51
(2) 異日間之精確度與準確度 ………………………………… 51
(3) 校正曲線（Calibration Curve）……………………………… 52
二、Indinavir之確效 ……………………………………………… 53
(1) 同日內之精確度與準確度 ………………………………… 53
(2) 異日間之精確度與準確度 ………………………………… 53
(3) 校正曲線 …………………………………………………… 54
(4) 絕對回收率（Absolute Recovery） ………………………… 54
第四節 藥品動態學之分析 …………………………………………… 56
第六章 結果 ………………………………………………………… 57
第一節 菊糖及Indinavir分析方法之確效…………………………… 57
一、灌流液中菊糖之測定 ……………………………………… 57
(1) 測定菊糖之偵測波長 ……………………………………… 57
(2) 校正曲線圖 ………………………………………………… 58
(3) 同日內之精密度與準確度 ………………………………… 59
(4) 異日間之精密度與準確度 ………………………………… 60
二、Indinavir之定量 ……………………………………………… 61
(1) 以Gradient Elution方式分析Indinavir之濃度 …………… 61
(2) 校正曲線…………………………………………………… 66
(3) 同日內之精密度與準確度 ………………………………… 67
(4) 異日間之精密度與準確度 ………………………………… 68
(5) 絕對回收率（Absolute Recovery）……………………… 69
第二節St. John’s wort對水份及Indinavir於大鼠小腸吸收的影響 … 70
一、 St. John’s wort對水份吸收的影響 ………………………… 70
(1) 水份吸收率（Water absorption ratio，WAR） ……………… 70
(2) 水份淨損量（Water net flux, WNF）………………………… 77
二、St. John’s wort對indinavir於大白鼠小腸吸收的影響 ……… 84
(1) 流出液中Indinavir之分析 ………………………………… 84
1. Indinavir的吸收百分率（absorption ratio，AR）………… 84
2. Indinavir的吸收廓清率（absorption clearance，CLa）…… 91
(2) 血漿中Indinavir之分析 …………………………………… 98
1. 肝門靜脈中Indinavir濃度的分析 ……………………… 98
2. 肝靜脈中Indinavir濃度的分析 ………………………… 99
三、St. John’s wort對Indinavir之藥品動態學參數的影響 ……106
(1) 肝門靜脈血漿內indinavir之藥品動態學參數 ……………106
(2) 肝靜脈血漿內indinavir之藥品動態學參數 ………………107
第七章 討論 ……………………………………………………… 113
第一節、 實驗步驟之相關探討 ……………………………………… 113
第二節、 灌流速度對小腸吸收的影響之探討 ……………………… 113
第三節、 St. John’s wort對小腸水份吸收的影響 …………………… 114
第四節、 St. John’s wort對indinavir在小腸吸收的影響 …………… 115
一、灌流流出液內indinavir濃度變化之探討 …………………… 115
二、血漿內indinavir濃度變化之探討 …………………………… 116
第五節、 Indinavir藥品動態學參數之探討 ………………………… 117
第六節、 影響小腸吸收indinavir的因素之探討 …………………… 119
一、Solvent Drag Effects ………………………………………… 119
二、pH值影響Indinavir的吸收 ………………………………… 119
三、Cytochrome P450（CYPs）分佈的影響 ……………………… 120
四、P-glycoprotein（Pgp）分佈的影響 …………………………… 121
五、灌流液中Indinavir濃度的影響……………………………… 123
六、長期或短期餵食St. John’s wort的影響 …………………… 123
第七節、 St. John’s wort萃取物之活性成分對CYP3A影響 ………… 124
第八節、 未來研究方向之探討 ……………………………………… 124
第八章 結論 ……………………………………………………… 125
第九章 附錄 ……………………………………………………… 127
第十章 參考文獻 ………………………………………………… 130

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