摘 要 大豆富含被稱為植物雌激素的異黃酮成分，包括大豆?(daidzin)、大豆?元 (daidzein)、染木? (genistin)、染木?元 (genistein)等，具有許多優越藥理活性。本研究探討人與大白鼠口服豆漿與大豆萃取物等大豆製品後之異黃酮代謝動力學及其對西藥cyclosporin及methotrexate (MTX) 動力學之影響。 四種大豆製品中異黃酮成分及其配醣體之定量係於酸水解之前、後分別利用本研究室開發之高效液相層析法，以梯度沖提進行分析。大白鼠口服市售大豆萃取物後，於各時間點以心臟穿刺採血。血清中異黃酮之定量，係於b-glucuronidase及sulfatase 分別水解前、後，利用高效液相層析法定量daidzein與genistein。結果顯示，大豆異黃酮主要以daidzein與genistein之結合態代謝物sulfates及glucuronides循環於體內，且有明顯的腸肝循環現象，結合態代謝物皆以sulfates為主。 九位健康受試者飲用豆漿後，分段收集48小時內之尿液，於以b-glucuronidase及sulfatase分別水解前、後，利用高效液相層析法定量daidzein、equol及genistein。結果顯示，尿中排出量最多者為daidzein結合態代謝物；其次為equol結合態代謝物；最少的是genistein結合態代謝物，三種異黃酮的結合態代謝物皆以sulfates為主。因此，異黃酮結合態代謝物的生物活性值得重視。 近年來全世界大豆膳食補充品之使用日益普遍，本研究以大白鼠為模型，探討大豆製品對治療窗狹窄的西藥cyclosporin及MTX動力學之影響。血中藥物濃度以螢光偏極免疫法 (FPIA) 定量。結果顯示，大白鼠併服大豆萃取物與味噌時，對口服cyclosporin之血藥面積及血峰濃度皆顯著降低。大白鼠併服大豆萃取物時，對口服MTX之血藥面積及滯留時間皆顯著增加，並導致死亡率的提升。因此，建議為確保療效及用藥安全，使用cyclosporin或MTX之病人最好避免併服大豆製品。; Abstract Soybean is abundant with isoflavones including daidzin, daidzein, genistin and genistein. Many beneficial pharmacological activities of these compounds had been reported. This study aimed to investigate the metabolic pharmacokinetics of these isoflavones after oral administrations of soy milk and soybean extract in rats and humans and to measure the effects on the pharmacokinetics of cyclosporine and methotrexate (MTX). The contents of isoflavones and their glucosides of four kinds of soybean products were determined prior to and after acid hydrolysis using a gradient HPLC method. Rats were given a commercial extract of soybean, then blood samples were withdrawn via cardiopuncture and assayed by HPLC method after hydrolysis with β-glucuronidase and sulfatase, respectively. Soy isoflavones were present in the bloodstream as sulfates and glucuronides, mainly as sulfates, which demonstrated enterohepatic circulation. Nine healthy volunteers were given soy milk and urinary recoveries of daidzein glucuronides and sulfates were investigated. The concentrations of daidzein, equol and genistein in urine were determined by HPLC after enzymatic hydrolysis with β-glucuronidase and sulfatase, respectively. Daidzein conjugates were the highest in urinary excretion followed by equol and genistein conjugates. Furthermore, the sulfates were predominant for all three isoflavones. In recent years, the soy dietary supplements are popularly used worldwide and easily available. This study investigated the effects of soy products on the pharmacokinetics of cyclosporine and MTX. The blood concentrations of cyclosporine and MTX were determined by monoclonal fluorescence polarization immunoassay (FPIA) method. The AUC0-t and Cmax of cyclosporine were significantly decreased after coadministration of soy extract and miso. In addition, the AUC0-t and MRT of MTX were significantly increased by coadministration of soy extract and the mortalities were supriseingly high. We suggested that for the sake of safety and efficacy of critical medicine, the coadministration of soy products with cyclosporine and MTX should be avoided.
