Moon Young Jin, Morris Marilyn E
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, New York 14260, USA.
Mol Pharm. 2007 Nov-Dec;4(6):865-72. doi: 10.1021/mp7000928. Epub 2007 Oct 31.
Little is known regarding pharmacokinetic (PK) or pharmacodynamic interactions of flavonoids with each other: this is of significance since multiple flavonoids are present in the diet and in dietary supplements. Our objective was to determine the effect of quercetin and (-)-epigallocatechin-3-gallate (EGCG), major flavonoids present in the diet, on the PK and bioavailability of biochanin A, a flavonoid with chemopreventive properties. BCA was administered to rats intravenously (5 mg/kg) or orally (16.67 or 50 mg/kg) with or without concomitant EGCG and quercetin. In vitro studies with the human intestinal Caco-2 and human hepatic HepG2 cell lines were performed to evaluate the effects of quercetin and EGCG on the cellular metabolism of BCA, and studies with human breast cancer MCF-7 cells that overexpress P-glycoprotein or BCRP (MCF-7/ADR and MCF-7/MX100 cells, respectively) or MDCK cells that express MRP2 (MDCK-MRP2) were performed to evaluate the effects of cellular efflux. An HPLC assay was used to determine plasma, urine, and cellular concentrations of BCA and the conjugated metabolites of BCA (following enzymatic hydrolysis). The coadministration of quercetin and EGCG significantly increased the BCA area under the plasma concentration vs time curve (AUC) in rats, after both iv and oral administration of BCA. The AUC of total BCA (unchanged + conjugated) was also increased. The increases in BCA AUC reflected predominantly increased bioavailability; this was true even after iv administration due to an apparent increase in the enterohepatic cycling of BCA. Our findings demonstrate for the first time that the administration of multiple flavonoids results in increased flavonoid bioavailability, as well as a decrease in clearance, potentially due to increased enterohepatic cycling.
关于黄酮类化合物之间的药代动力学（PK）或药效学相互作用，人们所知甚少：鉴于饮食和膳食补充剂中存在多种黄酮类化合物，这一点具有重要意义。我们的目标是确定饮食中主要的黄酮类化合物槲皮素和（-）-表没食子儿茶素-3-没食子酸酯（EGCG）对具有化学预防特性的黄酮类化合物生物chanin A（BCA）的PK和生物利用度的影响。将BCA静脉注射（5 mg/kg）或口服（16.67或50 mg/kg）给予大鼠，同时给予或不给予EGCG和槲皮素。用人肠道Caco-2细胞系和人肝脏HepG2细胞系进行体外研究，以评估槲皮素和EGCG对BCA细胞代谢的影响，并用过表达P-糖蛋白或BCRP的人乳腺癌MCF-7细胞（分别为MCF-7/ADR和MCF-7/MX100细胞）或表达MRP2的MDCK细胞（MDCK-MRP2）进行研究，以评估细胞外排的影响。采用HPLC测定法测定BCA的血浆、尿液和细胞浓度以及BCA的结合代谢物（酶水解后）。在静脉注射和口服BCA后，槲皮素和EGCG的共同给药显著增加了大鼠血浆浓度-时间曲线下BCA的面积（AUC）。总BCA（未改变的+结合的）的AUC也增加了。BCA AUC的增加主要反映了生物利用度的增加；即使在静脉注射后也是如此，这是由于BCA的肝肠循环明显增加。我们的研究结果首次表明，多种黄酮类化合物的给药导致黄酮类化合物生物利用度增加，以及清除率降低，这可能是由于肝肠循环增加所致。
