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

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

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