摘 要
葛根 (Puerariae Radix) 含豐富異黃酮成分，包括葛根素（puerarin）、大豆（daidzin）、大豆元（daidzein）等，具有優越藥理活性。本研究探討人與大白鼠口服葛根水煎劑或濃縮散劑後之代謝動力學及葛根對環孢靈及地高辛動力學之影響。
利用高效液相層析法，以梯度沖提，同時分析葛根水煎劑及濃縮散劑中葛根素、大豆及大豆元之含量。分析九種飲片之水煎劑及八種濃縮散劑之結果顯示，葛根水煎劑中，每公克飲片含葛根素、大豆和大豆元，分別為4.0 ± 0.7、0.8 ± 0.1及0.2 ± 0.05 mg，每公克濃縮散劑中之含量則為9.8 ± 0.7、1.4 ± 0.1 及0.4 ± 0.03 mg。
大白鼠口服葛根濃縮散劑，以心臟穿刺採血，血藥濃度之定量，係以-glucuronidase及sulfatase 分別水解後，利用高效液相層析法定量daidzein。結果顯示， daidzein結合態代謝物中以sulfates為主，而glucuronides較少。
十位受試者口服相等異黃酮含量之水煎劑及濃縮散劑後，36小時內分段收集尿液，經 -glucuronidase及sulfatase 分別水解後，利用高效液相層析法定量daidzein，計算尿中daidzein glucuronides及sulfates之累積排出量及其佔口服劑量之百分比。結果顯示，口服濃縮散劑後尿中daidzein glucuronides及daidzein sulfates之排出量，比水煎劑顯著減少了58.1 % 及51.4 %。
近年來中西藥併服情況日益普遍，對於治療窗狹窄之環孢靈及地高辛尤其值得關注。本實驗以大白鼠為模型，探討葛根對環孢靈及地高辛動力學之影響。環孢靈與地高辛之血中濃度，係以螢光偏極免疫法定量。研究結果顯示，大白鼠併服葛根散劑時，對靜注之地高辛血藥面積影響不大。大白鼠併服葛根水煎劑時，血液中環孢靈之血藥面積及血峰濃度顯著降低了62.8 %及62.2 %，而併服濃縮散劑時，顯著降低了74.9 % 及80.3 %，葛根明顯降低環孢靈之口服生可用率。因此，為確保療效及用藥安全，應避免併服環孢靈與葛根。

YI-ROU YEH
Graduate Institute of Chinese Pharmaceutical Science, China Medical College, Taichung, Taiwan, ROC.
ABSTRACT
Puerarin, daidzin and daidzein are bioactive isoflavone constituents of Puerariae Radix. This study aimed to investigate the metabolic pharmacokinetics of these isoflavones after oral administrations of traditional decoction and commercial extract of Puerariae Radix in rats and humans and to measure the effects on the pharmacokinetics of cyclosporine and digoxin.
Nine crude drugs and eight brands of commercial extracts of Puerariae Radix were purchased from the market and their contents of puerarin, daidzin and daidzein were determined by gradient HPLC. The contents of puerarin, daidzin and daidzein in traditional decoctions of each gram Puerariae Radix were 4.0 ± 0.7 mg, 0.8 ± 0.1 mg and 0.2 ± 0.05 mg, whereas those in each gram commercial extracts were 9.8 ± 0.7 mg, 1.4 ± 0.1 mg and 0.4 ± 0.03 mg, respectively.
Rats were given commercial extract of Puerariae Radix. Blood samples were withdrawn via cardiopuncture and assayed by HPLC method after enzymatic hydrolysis withβ-glucuronidsae and sulfatase, respectively. Daidzein sulfates were found predominantly in the bloodstream, whereas daidzein glucuronides presented in less amount.
Ten healthy male volunteers ingested traditional decoction and commercial extract which contain equivalent amount of isoflavones in a crossover design. The absorption was measured by urinary recoveries of daidzein glucuronides and sulfates within 36 h. The concentration of daidzein in urine was determined by HPLC after enzymatic hydrolysis with β-glucuronidsae and sulfatase, respectively. The cumulated urinary recoveries (% of dose) of daidzein glucuronides and sulfates after dosing commercial extract were significantly lower than those after dosing traditional decoction by 58.1 % and 51.4 %, respectively.In recent years, there has been a growing attention paid to interactions between herbs and pharmaceuticals, especially drugs with narrow therapeutic index. This study investigated the effects of Puerariae Radix on the pharmacokinetics of cyclosporine and digoxin. The blood concentrations of cyclosporine and digoxin were determined by FPIA method. No significant effect on pharmacokinetics of digoxin was found. The AUC0-t and Cmax of cyclosporine were significantly decreased by 62.8 % and 62.2 %, respectively, after coadministration with traditional decoction of Puerariae Radix and by 74.9 % and 80.3 %, respectively, after coadministration with its commercial extract. We suggested that for the sake of efficacy, the coadministration of Puerariae Radix with cyclosporine should be avoided.

附圖目錄………………………………………………………III
附表目錄………………………………………………………VII
中文摘要………………………………………………………XII
英文摘要………………………………………………………XIV
第一章 緒言…………………………………………………1
第二章 總論…………………………………………………4
第一節 葛根之本草學考察………………………………4
第二節 葛根之化學成分…………………………………8
第三節 葛根素、大豆與大豆元之結構與理化性質12
第四節 葛根之藥理活性考察……………………………15
第五節 葛根之動力學考察………………………………20
第六節 環孢靈（Cyclosporine）之特性………………22
第七節 地高辛（Digoxin）之特性 ……………………24
第三章 實驗部份……………………………………………26
第一節 實驗材料…………………………………………26
一、實驗試藥………………………………………………26
二、儀器設備………………………………………………28
三、實驗動物………………………………………………29
四、溶液製備………………………………………………29
第二節 實驗方法…………………………………………32
一、 葛根水煎劑及濃縮散劑中puerarin、daidzin 與
daidzein之HPLC定量分析…………………………32
二、大白鼠口服葛根濃縮散劑之動力學…………………37
三、葛根水煎劑與濃縮散劑於人體吸收之比較…………43
四、葛根水煎劑與濃縮散劑於大白鼠體內對環孢靈動
力學之影響………………………………………………47
五、葛根濃縮散劑於大白鼠體內對地高辛動力學之影響…50
六、葛根水煎劑對P-glycoprotein功能之影響……………52
第四章 結果與討論……………………………………………54
一、 葛根水煎劑及濃縮散劑中puerarin、daidzin 與
daidzein 之HPLC定量分析……………………………54
二、大白鼠口服葛根濃縮散劑之動力學……………………57
三、葛根水煎劑與葛根濃縮散劑於人體吸收之比較 ………61
四、葛根水煎劑與濃縮散劑於大白鼠體內對環孢靈、地高辛
動力學之影響………………………………………………65
參考文獻…………………………………………………………113
附錄………………………………………………………………124

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