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| 題 名 | 常用中西藥併用之交互作用臨床研究與風險評估=Clinical Study and Risk Evaluation of Herb-Drug Interaction |
|---|---|
| 編 次 | (2-1) |
| 作 者 | 鮑力恒; | 書刊名 | 中醫藥年報 |
| 卷 期 | 3 2014.12[民103.12] |
| 頁 次 | 頁(30)1-(30)58 |
| 分類號 | 418.1 |
| 關鍵詞 | 中西藥物交互作用; 代謝酵素; 運輸蛋白; Herb-drug interactions; Metabolite enzymes; Transporters; |
| 語 文 | 中文(Chinese) |
| 中文摘要 | 本研究計畫主要是基於之前體內外試驗的成果上,進一步地針對人體主要代謝酵素 CYP2C9有顯著抑制作用且經動物試驗證實與西藥有顯著交互作用的常用濃縮中藥(如:甘露飲)進行單劑量與多劑量中藥於健康自願者之臨床交互作用評估,以主要經由 CYP2C9代謝之西藥(如: fluvastatin)來進一步評估產生交互作用的風險。本研究計畫亦將針對臨床上最常用的 30種複方中藥製劑進行對癌症治療上重要的運輸蛋白 (如 P-gp)功能的影響作一系統性的探討及研究,包含動物體內的試驗成果;再更進一步地挑選具有最顯著功能調控的中藥複方來進行 P-gp受質藥物(如: fexofenadine)與多劑量中藥投予的人體臨床交互作用評估,以提供後續臨床上實際使用及評估的參考依據。 針對甘露飲影響人體主要代謝酵素 CYP2C9實驗方法為第一階段先給予受試者單一劑量之 fluvastatin (40mg)併用 16克的安慰劑,經過至少一星期的 washout period後繼續進行第二階段試驗,第二階段再同時給予單一劑量 fluvastatin (40mg)及單一劑量甘露飲 (16g);參與試驗者共 24人次。所有血液檢體將以高效液相層析質譜儀(LC/MS/MS)分析其中 nalbuphine之濃度,並以獲得數據計算相對生體可用率、濃度時間曲線下面積、最高血中濃度、達到最高濃度的時間以及排除半衰期等藥動學參數。 結果發現當受試者給予甘露飲併服 fluvastatin (66mg)後,受試者體內血漿之 fluvastatin 濃度與控制組相比,中藥組會在吸收相顯著升高,而由 fluvastatin動力學參數來看,fluvastatin體內最高濃度 (Cmax)由控制組的 139.85 ± 50.03 ng/mL,升高至 397.48 ± 245.09 (p < 0.01)。代表體內吸收藥物的總量的 AUCt,則由控制組的 317.94 ± 70.73 hr*ng/mL,升高至 477.29 ± 180.86 hr*ng/mL (p < 0.01),增加吸收達 1.5倍;而代表藥物清除速率的 Cl/F,由控制組的 131.24 ± 28.76 L/hr,減緩至 96.62 ± 36.83 (p < 0.01);顯示單一劑量 (16克)甘露飲併服 fluvastatin結果即發現 fluvastatin最高血中濃度及吸收量顯著高於口服 fluvastatin併用安慰劑者。 複方中藥影響 P-gp功能之實驗方法為口服給予大鼠複方中藥七天後,第八天給予 P-gp受質 fexofenadine (10mg/kg)。所有血液檢體將以高效液相層析質譜儀 (LC/MS/MS)分析其中之 fexofenadine濃度,在本實驗室已開發完成利用 fexofenadine-d6當內部標準品及蛋白質沉澱之前處理的方式來處理血漿檢體。於0.1 ml血漿檢體中, fexofenadine最低可定量濃度為 1 ng/mL。依目前結果, fexofenadine於血漿之分析方法均符合國際及國內分析確效的要求,此分析方法應可應用於相關藥物濃度之檢測及於動物藥物動力學研究之用。 動物試驗部份,已分析完成於體外實驗中具顯著 p-glycoprotein功能調控的前八種常用中藥複方之體內模式試驗。結果顯示連續服用七天的葛根湯、香砂六君子湯、小柴胡湯與川芎茶調散,再於第八天口服 fexofenadine (10mg/kg)之結果,對 P-gp的專一性受質 fexofenadine之曲線下面積會造成顯著影響,其中又以葛根湯影響最甚,下降約 67%。有鑑於國人目前服中藥的人數日益漸增,故此中西藥交互作用的問題於人體體內的影響,急需進一步的試驗確認來釐清此疑慮。 |
| 英文摘要 | Based on the results of herb-drug interactions of CYP2C9-metabolized drug in rats, the first purpose of this project is to conduct the interactions between administrating Gan Ru Yin at a single dose or multiple doses and fluvastatin in healthy human volunteers. The second purpose of this study was to evaluate the effects of 30 frequently used clinical Chinese herbal medicines on a P-gp in rats. The most effective candidates of Chinese herbal medicines would be chosen for further studies in human at a multiple doses. This study may provide useful information for medical professional in prescription and consultation to reduce the chance of adverse effects and improve the quality of medical care. To evaluate the drug-drug interaction between Chinese medicine, Gan-Lu-Yin (GLY) and marketed drug, fluvastatin. Healthy volunteers were included in this study for two stages treatments. For the first stage, subjects were orally co-administered with single dose of fluvastatin (40mg) with placebo. For the second stage, subjects were orally co-administered with single dose of fluvastatin (40mg) and single dose of GLY (16g). The plasma samples were analyzed for fluvastatin concentration with LC/MS/MS. The pharmacokinetic parameters, Cmax, AUC, and half-life were calculated and compared for the two stages to evaluate the herb-drug interaction between GLY and fluvastatin.When subjects were co-administered with GLY and fluvastatin, their plasma levels of fluvastatin were significantly higher than the ones of subjects co-administered with fluvastatin and placebo. The Cmaxs of fluvastatin of subjects administered with or without GLY were 397.48 ± 245.09 and 139.85 ± 50.03 ng/mL (p < 0.01), respectively. The extent of absorption (AUCt ) of fluvastatin of subjects co-administered with GLY and fluvastatin were also significantly increased to 150% compared to the ones of subjects co-administered with fluvastatin and placebo (477.29 ± 180.86 vs. 317.94 ± 70.73 hr*ng/mL, p < 0.01). The clearance (CL/F) of fluvastatin of subjects co-administered with GLY were also significantly decreased from the ones without GLY (131.24 ± 28.76 vs. 96.62 ± 36.83 L/hr, p < 0.01). Herb-drug interactions were initially found between Chinese medicine, Gan-Lu-Yin and Western medicines, fluvastatin. In vivo analysis of p-glycoprotein regulation with continuous administration of Chinese herbal medicines, Ko Ken Tang, Siang Sha Liu Jun Zi Tang, Xiao Chai Hu Tang or Chuan Chiung Cha Tiao San for seven days was completed. The concentration of the area under the curve (AUC) of the orally administered 10mg/kg fexofenadine showed significant effects. Ko Ken Tang, exhibited the most effect where it decreased 67% compared with the control group. In order to provide more useful information for the use of CHMs and the possible herb-drug interactionsfurther tests needed to be confirmed. |
本系統中英文摘要資訊取自各篇刊載內容。