頁籤選單縮合
題 名 | 常用中西藥同時併用之交互作用風險評估(2-1)=Chinese Medicines Affect the Activity of Hepatic Metabolic Enzymes(2-1) |
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作 者 | 胡幼圃; | 書刊名 | 中醫藥年報 |
卷 期 | 28:6 2010.09[民99.09] |
頁 次 | 頁95-130 |
分類號 | 418.1 |
關鍵詞 | 肝臟代謝酵素; 中西藥交互作用; 濃縮中藥; CYP450; UGT; Drug-drug interaction; |
語 文 | 中文(Chinese) |
中文摘要 | 研究目的: 針對人體主要第一相及第二相代謝酵素CYP1A2, CYP2D6, CYP2C9, CYP3A4及UGT2B7有顯著抑制作的常用濃縮中藥(如蒼耳散、正骨紫金丹、甘露飲及清心蓮子飲)進行動物試驗,確認其產生交互作用的風險。96年為本計畫第一年,執行主要範圍為CYP3A4及UGT2B7之部份。 研究方法: 1. 單一劑量常用濃縮中藥併服經CYP3A4代謝模式藥物(midazolam)之動物藥動試驗:控制組大鼠僅口服給予模式藥物midazolam 20mg/kg(藥品濃度5mg/ml),實驗組大鼠另外合併服用知柏地黃丸萃取液,給予大鼠知柏地黃丸的劑量為仿單標示人體平常服用劑量的5倍(0.33克/公斤體重)。控制組及實驗組於給藥後0, 2, 5, 15, 30, 45, 60, 90, 120, 180與240分鐘自大白鼠尾靜脈取血0.3ml並加入適量之肝素(heparin)。 2. 單一劑量濃縮中藥併服經UGT2B7代謝模式藥物(nalbuphine)之動物藥動試驗:控制組大鼠僅口服給予模式藥物Nalbuphine 20mg/Kg(溶於Q水,20mg/mL),實驗組大鼠另外合併服用桑菊飲,給予桑菊飲的劑量為仿單標示人體平常服用劑量的5倍(0.17克/公斤體重)。控制組及實驗組於最後 一次給藥後於0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12及24小時,自大白鼠尾靜脈取血 0.3 ml並加入適量之肝素(heparin),以防止凝血,利用超高速離心將血漿分離後置於-80 ℃冰箱冷凍。血液檢品的處理方法是採用串連質譜儀 高層液相分析儀的分析方法探針藥物在大鼠體內隨時間的變化分析後,即可以WinNonlin分析探針藥物於大鼠體內的藥動學參數。3. 大白鼠肝毒理組織切片觀察:動物試驗經餵食過中藥之大白鼠將進行大白鼠毒理組織切片觀察,以肝組織切片觀察其肝臟的變化以確認該中藥對肝臟的影響。 結果與討論: 1. 大白鼠口服midazolam同時併服知柏地黃丸後會使midzolam在體內之吸收量(AUCtotal)顯著增加1.39倍(p < 0.005),由50048 ± 8340增加為69592 ± 9945min*ng/mL;體內最高濃度(Cmax)也顯著升高1.36倍(p < 0.05),由565 ± 133 增加為767 ± 132 ng/mL;病理切片觀察發現,併服知柏地黃丸組HAI score(2.00 ± 0.00)有稍微上升,不過與控制組(1.50 ± 0.84)比較並未達顯著差異之程度。 2. 大白鼠口服nalbuphine同時併服桑菊飲後會使nalbuphine在體內之吸收量(AUCtotal)顯著增加2.90倍(p < 0.001),由39 ± 12增加為116 ± 16 hr*ng/mL;體內最高濃度(Cmax)也顯著升高3.31倍(p < 0.05),由18.0 ± 7.4 增加為59.6 ± 25.7 ng/mL;病理切片觀察發現,併服桑菊飲並不會有肝損傷發現,其HAI score(1.00 ± 1.10)與控制組(1.32 ± 0.82)比較並沒有顯著差異。由以上結果發現單劑知柏地黃丸及桑菊飲已明顯分別與midazolam及nalbuphine產生藥物-藥物交互作用,未來應再進一步以臨床試驗來確認。 |
英文摘要 | Aims: To evaluate the drug-drug interaction between Chinese medicine and marketed drug. This project is help to clarify the safety of Chinese medicine and then help the people keeping from hepatic injury when using Chinese medicines and synthetic agents. Methods: 1. SD rats PK study of single dose of midazolam and Zhi-bai-di-huang-wan (ZBDHW): 12 SD rats were randomly and equally divided into study and control group. 6 rats of study groups were orally given 20 mg/kg of midazolam and 0.33 mg/kg of ZBDHW and the other 6 SD rats were orally given 20 mg/kg of midazolam only. For both group, 0.3 ml of blood samples were taken from tail vein of rats at 2, 5, 15, 30, 45, 60, 90, 120, 180 and 240 minutes after dosing. 2. SD rats PK study of single dose of nalbuphine and Sang-ju-yin (SJY): 12 SD rats were randomly and equally divided into study and control group. 6 rats of study group were orally given 20 mg/kg of nalbuphine and 0.17 mg/kg of SJY and the other 6 SD rats of control group were orally given 20 mg/kg of nalbuphine only. For both group, 0.3 ml of blood samples were taken from tail vein of rats at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours after dosing. All the blood samples were expressed into plasma and stored at -80oC before assayed with LC/MS/MS. 3. Pathological observations of liver slices were also conducted to confirm the effects of target Chinese medicine to liver tissues. Results: 1. The extent of absorption (AUCtotal ) of midzolam in SD rats were significantly increased to 1.39 folds by ZBDHW (50048 ± 8340 vs. 69592 ± 9945 min*ng/mL, p< 0.005).The Cmax of midazolam in SD rats were also significantly increased 1.36 folds (565 ± 133 vs. 767 ± 132 ng/mL, p < 0.05). No significant pathological observation was found between study and control groups. 2. The extent of absorption (AUCtotal ) of nalbuphine in SD rats were significantly increased to 2.90 folds by SJY (39 ± 12 vs. 116 ± 16 hr*ng/mL, p < 0.001).The Cmax of nalbuphine in SD rats were also significantly increased 3.31 folds (18.0 ± 7.4 vs. 59.6 ± 25.7 ng/mL, p < 0.05). No significant pathological observation was found between study and control groups. Conclusions: Significant drug-drug interactions were found between Chinese and Western medicines. |
本系統中英文摘要資訊取自各篇刊載內容。