桑色素之藥物動力學及其對環孢靈吸收之影響; Morin pharmacokinetics and the the effect of morin on cyclosporin absorption

中國醫藥大學機構典藏 China Medical University Repository, Taiwan > 藥學院 > 藥物化學研究所 > 博碩士論文 > Item 310903500/24030

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題名:	桑色素之藥物動力學及其對環孢靈吸收之影響;Morin pharmacokinetics and the the effect of morin on cyclosporin absorption
作者:	蔡玉娟;Tsai Yu-Chuan
貢獻者:	中國醫藥學院藥物化學研究所
關鍵詞:	桑色素;環孢靈;Morin;cyclosporin
日期:	1999
上傳時間:	2009-12-02 14:20:24 (UTC+8)
摘要:	中文摘要桑色素為一天然黃酮類，具有許多優越的藥理活性。本研究以紐西蘭白兔口服投予及靜脈注射桑色素，以瞭解其動力學行為。血清中桑色素之代謝物以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方法係採用Cosmosil RP-18 column，移動相的組成為乙? : 0.2 ％磷酸水溶液（28 ： 72, v/v），流速為1.0 ml /min ，偵測波長設定在250 nm，ethyl paraben為內標準，為一敏感度高且簡單方便的分析方法，同日內及異日間之確效結果顯示精確度良好，此分析方法的定量極限 (LOQ) 為1.56 μg/ml，偵測極限 (LOD) 為0.39μg/ml 。兔子靜脈注射桑色素10.0 mg/kg與20.0 mg/kg兩種劑量後，平均血藥面積分別為2144.3與19266.5 nmol· min·ml-1，兩劑量的排除半衰期、全身清除率、分佈體積及平均滯留時間等參數之差異，皆達統計上的意義 (p<0.05)。兔子口服投予桑色素50.0 mg/kg時，只有少數檢品偵測出原型桑色素，因此無法計算其動力學參數。口服桑色素100.0 mg/kg後，血藥面積為5473.9 nmol· min·ml-1。血峰濃度、AUCs和劑量不呈一定的比例，此結果顯示較高劑量下，代謝?有飽和的現象，因此桑色素在兔體內之行為是非線性動力學。環孢靈為一強效之免疫抑制劑，治療指數極小。平均生體可用率約30 %，首渡代謝主要與P-glycoprotein (P-gp) 及CYP3A4有關。本研究以大白鼠為模型，探討桑色素對環孢靈吸收之影響。血中環孢靈之測定，以螢光偏極免疫法定量之。七隻大白鼠併服桑色素之結果顯示，其中四隻血液中環孢靈之AUC 0-t明顯增加65.1 % (p= 0.047)；另外三隻血液中環孢靈之AUC 0-t明顯減少32.3 % (p= 0.02)。此結果顯示桑色素對環孢靈吸收的影響因個體而有極大差異。當桑色素或含桑色素之天然藥物與環孢靈併服時，需要小心監測環孢靈之血中濃度。體外翻腸試驗結果顯示，桑色素與槲皮素對P-gp為抑制作用，柚皮?元則對P-gp的活性無影響。; Abstract Morin is a bioactive flavonoid and possesses many beneficial pharmacological activities. The pharmacokinetics of morin was investigated in New Zealand white rabbits after oral and intravenous administrations. Metabolites of morin in serum were hydrolyzed anaerobically by incubation with β-glucuronidase/sulfatase at 37 ℃ for 4 hr with the addition of ascorbic acid. A sensitive and simple HPLC method for the determination of morin in serum was developed. The analysis was performed on Cosmosil RP-18 column with a mobile phase consisting of acetonitrile: 0.2 % ortho-phosphoric acid solution (28: 72, v/v). The method employed a flow rate of 1.0 ml/min with detection at 250 nm and ethyl paraben was used as the internal standard. The precision and accuracy of the method were good for intra-day and inter-day assays. The limit of detection ( LOD ) was 0.39 μg/ml and the limit of quantitation ( LOQ ) was 1.56 μg/ml. After intravenous administration of morin (10.0 mg/kg and 20.0 mg/kg) to rabbits, the AUCs were 2144.3 and 19266.5 nmol·min·ml-1, respectively. The Vd, Cl, t1/2 and MRT were significantly different between two doses . After oral dosing of morin (50.0 mg/kg) to rabbits, free form morin was detected in few samples, no attempt had been made to calculate the parameters. After oral dosing of morin (100.0 mg/kg) to rabbits, the AUC was 5473.9 nmol· min·ml-1. The Cmax and AUCs did not increase proportionally with dose, indicating that morin demonstrated nonlinear pharmacokinetics. The MRT after high dose was significantly much higher than that after low dose, suggesting that the metabolic process had been saturated at higher dose. Cyclosporin is a potent immunosuppressive agent with narrow therapeutic range. The mean systematic bioavailibility is about 30 %. CYP3A4 and P-glycoprotein are involved in the first pass extraction of cyclosporin. Blood cyclosporin concentrations were determined by FPIA method. To investigate the effect of morin on absorption of cyclosporin, seven rats were orally given cyclosporin alone or coadministration with morin. The result showed that the AUC0-t was increased by 65.1 % (p=0.047) in four rats, and decreased by 32.3 % (p=0.02) in three rats. Therefore, when morin was coadministered with cyclosporin, the blood cyclosporin concentration should be carefully monitored. In vitro everted sac study showed that morin and quercetin were inhibitors of P-glycoprotein, whereas naringenin was not a P-glycoprotein modulator.
顯示於類別:	[藥物化學研究所] 博碩士論文

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