常用中西藥併用之交互作用 臨床研究與風險評估

鮑力恒
國防醫學院
中藥裡含有影響肝臟代謝酵素與運輸蛋白的活性成份，其影響肝臟代謝和運輸蛋白功能的可能性甚高，故極需評估常用中藥併用西藥產生交互作用之風險。於我們過去研究成果中，發現許多中藥成份可有效抑制或促進Phase I 代謝酵素CYP1A、CYP3A、CYP2C9、CYP2D6及Phase II代謝酵素UGT2B的活性；更在健康受試者的臨床試驗亦顯示：蒼耳散複方濃縮中藥製劑在連續服用臨床常用治療劑量下七天後，確實可增加CYP3A的專一性受質藥物midazolam的曲線下面積及最高血中濃度，增加幅度1.37倍及1.52倍。而在CYP2C9的體外試驗結果顯示：甘露飲抑制CYP2C9活性達82.2 ± 8.7%；動物試驗結果顯示，甘露飲複方濃縮中藥製劑在餵食大鼠臨床常用劑量連續七天後，fluvastatin在體內血中最高濃度及曲線下面積各增加1.7及1.8倍。在運輸蛋白方面，我們亦完成中藥藥引中之純成分對重要的efflux transporters，如：P-gp、MRP1體外及體內活性影響之研究，結果顯示具有相當多的中藥純成分分別對此二種運輸蛋白活性具有顯著的抑制作用。
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20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。
關鍵字：中藥、中西藥物交互作用、代謝酵素、運輸蛋白

Clinical Study and Risk Evaluation of Herb-Drug Interaction

Li-Heng-Pao
National Defense Medical Center
Many ingredients in the Chinese herbal medicine (CHMs) could influence the activity of metabolic enzymes in the liver. Therefore, investigation on the risks of herb-drug interactions is necessary. In our previous studies, ingredients altering function of CYP1A,CYP3A, CYP2C9, CYP2D6 and UGT2B were observed in vitro and in vivo experiments. The results in human showed that the AUC and Cmax of midazolam increased 37% and 52% after 7 days administration of Tsang-Eel-San, respectively. Besides, Gan Ru Yin inhibits the functional activities of CYP2C9 up to 82.2 % in vitro. The AUC and Cmax of fluvastatin increased 70% and 80% after 7 days administration of Gan Ru Yin, respectively in rats. For efflux transporters, a systemic evaluation indicated that abundant Chinese herbal enhancers inhibit the functions of P-gp and MRP1 both in vitro and in vivo.
Based on the results of herb-drug interactions described above, the interactions between administrating Gan Ru Yin and fluvastatin at a single dose or multiple doses in healthy human volunteers will be carried out. The second part of this study was to evaluate the effects of 20 frequently used compounded CHMs on the function of P-gp in rats. The most effective Chinese herbal medicines in rats 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.
關鍵字：Chinese herbal medicines; herb-drug interactions; metabolite enzymes; transporter