Indican於大鼠之代謝動力學與其對Methotrexate動力學之影響; Pharmacokinetics of Indican and Its Effect on Methotrexate Pharmacokinetics in Rats

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題名:	Indican於大鼠之代謝動力學與其對Methotrexate動力學之影響;Pharmacokinetics of Indican and Its Effect on Methotrexate Pharmacokinetics in Rats
作者:	詹淑玲;Shu-Ling Chan
貢獻者:	中國醫藥大學：藥物化學研究所碩士班
關鍵詞:	板藍根;代謝動力學;多重藥物抗藥性蛋白;有機陰離子運輸蛋白;indican;indoxyl sulfate;isatis indigotica L.;interaction;pharmacokinetics
日期:	2006-05-22
上傳時間:	2009-08-13 09:37:23 (UTC+8)
摘要:	Indican為藍色染料indigo、indirubin的前驅物，存在於中藥板藍根、大青葉中。板藍根、大青葉之基原為十字花科（Cruciferae）菘藍Isatis indigotica FORTUNE的乾燥根與葉，為臨床常用中藥，具清熱解毒、涼血利咽之功效，在SARS期間使用量曾驟增。Indican在體內會代謝成腎毒性物質indoxyl sulfate。本研究探討indican於大鼠體內的代謝動力學。大鼠以交叉設計給藥，分別口服20, 40 mg/kg indican及靜脈注射10 mg/kg indican，於特定時間點由心臟採血，血清以HPLC方法定量indican及indoxyl sulfate。結果顯示，indican在大鼠體內會以原型吸收，但主要代謝成indoxyl sulfate。 Methotrexate（MTX）為一治療指數狹窄的抗癌藥及免疫抑制劑，為多重藥物抗藥性蛋白/有機陰離子運輸蛋白( MRPs/OATs ) 之受質。Indoxyl sulfate亦賴MRPs/OATs為運送蛋白。大鼠以平行設計給藥，探討分別併服10, 20及40 mg/kg indican對MTX動力學之影響，MTX血中濃度以螢光偏極免疫法（FPIA）定量，並利用非室性藥動學模式計算動力學參數，結果顯示，併服20 及40 mg/kg indican對MTX之血薬面積及滯留時間皆顯著提高。可以推論indoxyl sulfate在大鼠體內會與MTX競爭共同的運送蛋白，因而導致MTX的血藥面積增加與滯留時間延長。因此建議接受MTX治療的病人應避免併用含indican成分之中藥，以確保用藥安全。 Indican (indoxyl-β-D-glucoside), a precursor of the blue dyes indigo and indirubin, is abundant in the roots and leaves of Isatis indigotica L., a popular Chinese herb, which was increasingly used by the public during the SARS panic. This study aimed to investigate the pharmacokinetics of indican and furthermore, the effect of coadministration of indican on the absorption and disposition of methotrexate (MTX), a bicarboxylate antimetabolite with narrow therapeutic window, was evaluated. Indican was orally administered to male Sprague-Dawley rats at doses of 20.0 and 40.0 mg/kg. The blood samples were withdrawn via cardiopunture and assayed by HPLC method for the concentrations of indican and indoxyl sulfate after deproteinization. Our results showed that indican was absorbed per se and mostly metabolized into indoxyl sulfate in rats. Rats were orally given MTX with and without indican at doses of 10.0, 20.0 and 40.0 mg/kg in a parallel design. The blood concentrations of MTX were assayed by fluorescence polarization immunoassay (FPIA) method. Pharmacokinetic parameters were calculated using noncompartment model of WINNONLIN. The results study showed that coadministration of 20.0 and 40.0 mg/kg indican significantly increased the area under the curve (AUC0-t) and mean residence time (MRT) of MTX. In conclusion, indoxyl sulfate, a substrate of MRPs (multidrug resistance-associated proteins) and OATs (organic anion transporters), may compete MRPs/OATs with MTX to result in the delayed elimination of MTX. We suggested that for the sake of safety, the coadministration of indican-containing herbs with MTX should be avoided.
顯示於類別:	[藥物化學研究所] 博碩士論文

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