槲皮素與桑色素於大白鼠之動力學及其對地高辛動力學之影響; Pharmacokinetics of Quercetin, Morin and Their Effects on Digoxin Pharmacokinetics

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題名:	槲皮素與桑色素於大白鼠之動力學及其對地高辛動力學之影響;Pharmacokinetics of Quercetin, Morin and Their Effects on Digoxin Pharmacokinetics
作者:	何泓璟;Hong-Jing Ho
貢獻者:	中國醫藥學院中國藥學研究所
關鍵詞:	槲皮素;桑色素;結構異構物;非線性動力學;地高辛;螢光偏極免疫法;quercetin;morin;isomeric;nonlinear pharmacokinetics;digoxin;FPIA
日期:	1990
上傳時間:	2009-12-02 11:53:25 (UTC+8)
摘要:	槲皮素與桑色素同屬flavonol?元，兩者互為結構異構物，皆具有許多優越的藥理活性。因此本研究以大白鼠來比較槲皮素與桑色素口服給藥後之動力學，探討其吸收與代謝之差異。此外，各以兩種劑量探討兩者劑量之依存性。血清中槲皮素或桑色素之代謝物以β-glucuronidase/sulfatase在無氧及添加維生素C之條件下，於37 ℃水解4小時，再以HPLC定量。本研究建立的HPLC方法為一敏感度高且簡單方便的分析方法。槲皮素在50 mg/kg及100 mg/kg兩劑量口服後，血中原型藥極微，槲皮素之吸收不佳，且大白鼠間之個體差異明顯。桑色素以25 mg/kg 及50 mg/kg 兩劑量口服後，高劑量的原型桑色素平均血峰濃度(Cmax)及平均血藥面積(AUC0-t)，約為低劑量的二十六倍及三十六倍。桑色素結合態之代謝物的平均血藥面積(AUC0-t)相差僅達3倍，而且口服後三十分鐘內之平均血藥面積(AUC0-30)，並無明顯差異。此結果顯示較高劑量下，代謝?有飽和的現象，因此桑色素在大白鼠體內之行為是非線性動力學。地高辛為一強心配醣體，治療指數極低。於大白鼠體中，地高辛同為CYP3A4與P-glycoprotein (Pgp)的受質。為了評估槲皮素、桑色素對地高辛動力學之影響，本實驗採交叉設計，一次單服地高辛，另一次併服50 mg/kg和100 mg/kg的槲皮素或桑色素。血清中地高辛濃度利用螢光偏極免疫法定量。除了有些大白鼠於低劑量併服時，地高辛的血藥面積(AUC0-t)呈現增加外，於併服槲皮素或桑色素後，地高辛的血藥面積(AUC0-t)皆呈現顯著降低。因此，地高辛與槲皮素、桑色素或含有此些成分之食物併服時，為了用藥安全及療效之考量，地高辛的血中濃度須要小心監測，以供劑量調整之參考。; Quercetin and morin are isomeric bioactive flavonoids possessing many beneficial pharmacological activities. The pharmacokinetics of quercetin and morin were investigated and compared in rats. The dose dependency was studied by using two dosages for both quercetin and morin, respectively. The serum were hydrolyzed anaerobically by incubation with β-glucuronidase/sulfatase at 37℃ in the presence of ascorbic acid to release quercetin or morin from their glucuronides. A simple, sensitive, and accurate HPLC method was developed for determination of quercetin or morin in serum. After oral dosing 50 mg/kg and 100 mg/kg quercetin, substantially no free form quercetin was detected. The presence of quercetin glucuronides indicated poor absorption and significant inter-individual variation. After oral dosing 25 mg/kg and 50 mg/kg morin, the Cmax and AUC0-t of morin were increased by 26 folds and 36 folds, respectively, when the dose was doubled, whereas for morin glucuronides, although the AUC0-t was increased by 3 folds, the early exposure AUC0-30 revealed no significant increase. The results indicated that morin displayed nonlinear pharmacokinetics and suggested the metabolic process had been saturated at higher dose. Digoxin is a potent cardiac glycoside with narrow therapeutic index. It was reported as substrates of both CYP3A4 and P-glycoprotein (Pgp) in rat. To investigate the effects of quercetin and morin on digoxin pharmacokinetics, rats were orally given digoxin (0.04 mg/kg) alone and coadministered with 50 mg/kg and 100 mg/kg quercetin or morin in crossover designs. Serum digoxin concentrations were determined by FPIA method. The AUC0-t of digoxin were signicantly decreased after various coadministrations except in some rats whose AUC0-t significant decrease after coadministration with low dose of quercetin or morin. Therefore, when quercetin, morin or food containing them was coadministered with digoxin, for the sake of safty and efficacy, the serum digoxin concentration should be carefully monitored.
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