Quercetin significantly decreased cyclosporin oral bioavailability in pigs and rats
Quercetin significantly decreased cyclosporin oral bioavailability in pigs and rats
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DOI：
10.1016/s0024-3205(02)02235-x
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发表时间：
2002-12-06
期刊：
影响因子：
6.1
通讯作者：
Chao, PDL
中科院分区：
文献类型：
--
作者：
Hsiu, SL;Hou, YC;Chao, PDL
环孢素是一种具有窄治疗窗口的免疫抑制剂，是CYP3A4和p -糖蛋白（Pgp）的底物。槲皮素是CYP3A4的抑制剂和Pgp的调节剂。本研究旨在测定槲皮素对环孢素在猪和大鼠体内吸收和处置的影响。猪和大鼠分别口服环孢素（Sandimmune, 10 mg/kg），同时或不同时给予槲皮素（50 mg/kg）。采用特异性单克隆荧光偏振免疫分析法测定血液样品中的环孢素浓度。采用WINNONLIN软件进行非区室分析，计算药代动力学参数。采用配对Student’st检验进行统计学比较。采用膨出肠囊法研究槲皮素对肠道Pgp功能的影响。槲皮素共给药显著降低环孢素在猪和大鼠体内的AUC(0-3)（时间0-3 h的浓度-时间曲线下面积）和AUC(0-t)（时间0-最后一点的浓度-时间曲线下面积）分别降低56%和43%，表明槲皮素共给药显著降低环孢素的口服生物利用度。然而，倒置囊研究表明，槲皮素显著抑制肠道Pgp的功能。建议将槲皮素或含槲皮素的膳食补充剂或草药与环孢素或其他由Pgp和/或CYP3A4介导的吸收和代谢的药物同时使用时应密切监测。(C) 2002年Elsevier Science Inc.出版
Cyclosporin, an immunosuppressant with a narrow therapeutic window, is a substrate for both CYP3A4 and P-glycoprotein (Pgp). Quercetin is an inhibitor of CYP3A4 and a modulator of Pgp. This study aimed to measure the effect of quercetin on the absorption and disposition of cyclosporin in pigs and rats. Cyclosporin (Sandimmune(R), 10 mg/kg) was orally administered with and without a concomitant dose of quercetin (50 mg/ kg) to pigs and rats. Cyclosporin concentrations in blood samples were determined by a specific monoclonal fluorescence polarization immunoassay. The pharmacokinetic parameters were calculated by noncompartmental analysis using WINNONLIN. A paired Student's t-test was conducted for statistical comparison. A study using the everted intestinal sac was carried out to evaluate the effect of quercetin on the function of intestinal Pgp. The coadministration of quercetin significantly decreased cyclosporin AUC(0-3) (area under the concentration-time curve from time zero to 3 h) by 56% and AUC(0-t) (area under the concentration-time curve from time zero to the last point) by 43% in pigs and rats, respectively, indicating that the coadministration of quercetin significantly decreased cyclosporin oral bioavailability. However, the inverted sac study showed that quercetin significantly inhibited the function of intestinal Pgp. It is suggested that concurrent use of quercetin or quercetin-containing dietary supplement or herbs with cyclosporin or other medications whose absorption and metabolism are mediated by Pgp and/or CYP3A4 should require close monitoring. (C) 2002 Published by Elsevier Science Inc.