以清醒動物微透析技術探討富含異黃酮中草藥食品與phenytoin之交互作用

中國醫藥大學機構典藏 China Medical University Repository, Taiwan > 藥學院 > 藥用化妝品學系暨碩士班 > 研究計畫 > Item 310903500/13139

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題名:	以清醒動物微透析技術探討富含異黃酮中草藥食品與phenytoin之交互作用
作者:	江秀梅(Hsiu-Mei Chiang);李珮端(Pei-Dawn Lee Chao);侯鈺琪(Hou,Yu-Chi)
貢獻者:	藥學院藥用化妝品學系
關鍵詞:	葛根;大豆;交互作用;Pueraria lobata;Soy, Drug interaction;Phenytoin;Caco-2
日期:	2007-07-31
上傳時間:	2009-09-01 16:15:27 (UTC+8)
摘要:	異黃酮(Isoflavone)為黃酮類(flavonoid)的一種，因異黃酮結構與動物雌激素相似，能與雌激素受體結合發揮弱雌激素作用，且對雌激素有雙向調節的功能，因此被稱為植物雌激素(phytoestrogen)。流行病學研究顯示，攝取較多富含異黃酮食物的國家，如日本、中國等亞洲國家之心血管疾病及癌症發生率較低，尤其有助於乳癌、卵巢癌、前列腺癌等與性激素有關的癌症，亦有臨床研究顯示此些異黃酮對緩解更年期症狀及防治骨質疏鬆症具明確療效。異黃酮主要分佈於豆科植物，大豆及葛根及即為其中具代表性者，大豆中異黃酮成分只含0.1-0.3%，而葛根所含的異黃酮成分占約8%。因此葛根與大豆萃取物為目前台灣市場頗受歡迎之健康食品。Phenytoin(PHT)為治療強直性陣攣型癲癇常用之藥物，治療指數狹窄，若血中濃度過高易致神經毒性，已有報告指出抗藥性常是造成療效不佳之主因，而BBB上的Pgp與MRPs之過度表現與抗藥性有關，另有研究指出MRP1與MRP2是其中主要的表現蛋白。許多研究顯示，異黃酮化合物主要以硫酸及葡萄糖醛酸結合態代謝物循環於血流中，近來更發現其外排與MRP1、MRP2、MRP3等運送蛋白有關，而PHT則與MRP1、MRP2等運送蛋白有關。吾人臆測異黃酮化合物與PHT併服時會競爭MRP1及MRP2，導致動力學交互作用。本研究擬以大鼠為模型，探討併服富含異黃酮之大豆與葛根對 PHT動力學之影響。本計畫擬利用交叉設計，予大白鼠分別單獨口服、靜脈注射PHT及分別併服大豆萃取物與葛根水煎劑，定時自心臟穿刺採血，PHT之血中濃度以HPLC-UV定量。血中藥物濃度數據以WINNONLIN軟體計算動力學參數，並以ANOVA統計組間差異。結果發現大豆萃取物可顯著延長口服 PHT之暴露，但對於靜脈注射之PHT之動力學則無影響；另外，葛跟對於口服PHT之動力學參數亦無顯著之影響。另外為進一步研究其交互作用之部位及機轉，以表現MRPs與OATs等運輸蛋白之細胞株Caco-2，進一步探索交互作用之機轉。本研究可了解併服富含異黃酮中草藥及食品對PHT之動態學之影響及交互作用之機轉，對長期服用PHT病患之臨床療效或安全極具參考價值。 The structures of isoflavones, a class of flavonoids, are similar to estrogen and recognized as phytoestrogen. In epidemiological studies, the morbidities of cancer and cardiovascular disease were found lower in countries consuming more isoflavon-rich diet, like Japan and China. The beneficial effects of isoflavones on menopausal symptoms and osteoporosis have been reported. Isoflavones are distributed in legumes like soybean and Pueraria Radix (PR), the roots of Pueraria lobata OWHI. The contents of isoflavones in soya are 0.1-0.3% and 8% in PR. Nowadays, extracts of soya and PR are popular heath foods in Taiwan market. Phenytoin (PHT) is used as an antiepileptic drug for generalized tonic-clonic seizure with narrow therapeutic window. Supratherapeutic level often induced neurotoxicity. Drug resistance always caused poor efficacy of antiepileptics and the overexpressions of Pgp and MRPs at BBB were associated to the resistance. In addition, MRP1 and MRP2 were reported the major protein expressed in this drug resistance. In our previous study, isoflavones were found predominantly as sulfates and glucuronides in the bloodstream, instead of their aglycones. The conjugated metabolites were reported as substrates of multidrug resistance proteins (MRPs) and organic anion transporters (OATs). Phenytoin is a substrate of MRPs and Pgp. The sulfates and glucuronides of isoflavones may compete for the transporters with phenytoin. This study investigated the effects of soy extract and PR decoction on the pharmacokinetics of phenytoin in rats. The blood concentration of PHT was determined by an HPLC method and the pharmacokinetic parameters were calculated using noncompatment model of WINNOLIN. The results indicated that soy extract would prolong the exposure of oral administration of PHT, but not that of intravenous PHT. In addition, PR would not alter the pharmacokinetics of PHT. The mechanisms of these herb-drug interactions were investigated using cells expressing MRPs or OATs, eg. Caco 2 cells. Through this study, it is anticipated to understand the effect and mechanism of soy product and PR on the pharmacokinetics of phenytoin. Furthermore, we attempt to establish an in vivo and in vitro model for herb-drug interaction studies.
顯示於類別:	[藥用化妝品學系暨碩士班 ] 研究計畫

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