Impact of quercetin‑induced changes in drug‑metabolizing enzyme and transporter expression on the pharmacokinetics of cyclosporine in rats.
Impact of quercetin‑induced changes in drug‑metabolizing enzyme and transporter expression on the pharmacokinetics of cyclosporine in rats.
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槲皮素诱导的药物代谢酶和转运蛋白表达变化对环孢素在大鼠体内药代动力学的影响
DOI：
10.3892/mmr.2016.5616
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发表时间：
2016-10
影响因子：
3.4
通讯作者：
Shi S
中科院分区：
文献类型：
--
作者：
Liu Y;Luo X;Yang C;Yang T;Zhou J;Shi S
本研究的目的是评估槲皮素（Que）是否调节小肠和肝脏中药物代谢酶（DME）和药物转运蛋白（DT）的mRNA和蛋白质表达水平，从而改变环孢素（CsA）在大鼠体内的药代动力学特征。该两部分研究评价了存在或不存在Que（实验I）以及DME和DT参与（实验II）时CsA的药代动力学特征。在实验I中，24只大鼠在第1天接受CsA（10 mg/kg）单次给药，在第3-8天接受Que（25、50和100 mg/kg/天;每组8只大鼠）单次给药，并在第9天同时接受CsA/Que。在实验II中，在25岁时口服Que后，分析了大鼠小肠和肝脏中细胞色素P（CYP）3A 1、CYP 3A 2、UDP葡萄糖醛酸转移酶家族1成员A复合物位点、有机阴离子转运多肽（OATP）2B 1、OATP 1B 2、P-糖蛋白、乳腺癌耐药蛋白和多药耐药相关蛋白2的mRNA和蛋白表达水平，50和100 mg/kg，存在或不存在CsA（10 mg/kg），连续7天。Que（25、50和100 mg/kg）可使CsA最大血药浓度分别降低46、50和47%，且呈剂量依赖性。最后可测浓度的曲线下面积和无限时间的曲线下面积分别减少了21和16%、30和33%、33和34%（P<0.01）。但Que对小肠和肝脏中上述DMEs和DTs的mRNA和蛋白表达水平均呈剂量依赖性抑制（P<0.01）。结果表明，Que能够降低大鼠多次伴随给药后CsA的生物利用度。肠和肝DME和DT的重叠调节以及DME-DT相互作用是这些观察结果的潜在解释。
The aim of the present study was to evaluate whether quercetin (Que) modulates the mRNA and protein expression levels of drug-metabolizing enzymes (DMEs) and drug transporters (DTs) in the small intestine and liver, and thus modifies the pharmacokinetic profile of cyclosporine (CsA) in rats. This two-part study evaluated the pharmacokinetic profiles of CsA in the presence or absence of Que (experiment I) and the involvement of DMEs and DTs (experiment II). In experiment I, 24 rats received single-dose CsA (10 mg/kg) on day 1, single-dose Que (25, 50 and 100 mg/kg/day; eight rats in each group) on days 3–8, and concomitant CsA/Que on day 9. In experiment II, the mRNA and protein expression levels of cytochrome P (CYP)3A1, CYP3A2, UDP glucuronosyltransferase family 1 member A complex locus, organic anion-transporting polypeptide (OATP)2B1, OATP1B2, P-glycoprotein, breast cancer resistance protein, and multidrug resistance-associated protein 2 in the small intestine and liver of rats were analyzed following oral administration of Que at 25, 50 and 100 mg/kg in the presence or absence of CsA (10 mg/kg) for seven consecutive days. Co-administration of Que (25,50 and 100 mg/kg) decreased the maximum serum concentration of CsA by 46, 50 and 47% in a dose-independent manner. In addition, the area under the curve to the last measurable concentration and area under the curve to infinite time were decreased, by 21 and 16%, 30 and 33%, and 33 and 34% (P<0.01), respectively. However, the mRNA and protein expression levels of the above-mentioned DMEs and DTs were inhibited by Que in a dose-dependent manner (P<0.01) to a similar extent in the small intestine and liver. It was demonstrated that Que was able to reduce the bioavailability of CsA following multiple concomitant doses in rats. Overlapping modulation of intestinal and hepatic DMEs and DTs, as well as the DME-DT interplay are potential explanations for these observations.
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UGT多态性作为固体器官移植中的生物标志物的影响。
DOI：
10.1016/j.cca.2012.01.031
发表时间：
2012-09-08
期刊：
Clinica chimica acta; international journal of clinical chemistry
影响因子：
--
作者：
Dupuis R;Yuen A;Innocenti F
通讯作者：
Innocenti F
影响因子：
2.7
作者：
Choi, JS;Choi, BC;Choi, KE
通讯作者：
Choi, KE
影响因子：
4.1
作者：
Cai, X.;Fang, Z.;Zhai, G.
通讯作者：
Zhai, G.
影响因子：
7.3
作者：
Fu, Jiping;Tjandra, Meiliana;Sweeney, Zachary K.
通讯作者：
Sweeney, Zachary K.
影响因子：
6.1
作者：
Hsiu, SL;Hou, YC;Chao, PDL
通讯作者：
Chao, PDL