Relevance of Breast Cancer Resistance Protein to Pharmacokinetics of Florfenicol in Chickens: A Perspective from In Vivo and In Vitro Studies.
Relevance of Breast Cancer Resistance Protein to Pharmacokinetics of Florfenicol in Chickens: A Perspective from In Vivo and In Vitro Studies.
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DOI：
10.3390/ijms19103165
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发表时间：
2018-10-15
影响因子：
5.6
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Liu Y;Guo L;Zloh M;Zhang Y;Huang J;Wang L
氟苯尼考（flfenicol， FFC）是一种有价值的硫胺霉素合成氟化衍生物，广泛用于治疗食用动物的传染病。本研究的目的是研究FFC是否是乳腺癌耐药蛋白（BCRP）的底物，以及这种转运体是否影响FFC的口服有效性。利用MDCK-chAbcg2细胞进行体外转运实验，评估BCRP介导的鸡FFC转运，并通过BCRP抑制剂吉非替尼单独或联合使用的体内药代动力学实验，研究BCRP在口服FFC转运中的作用。根据美国食品和药物管理局（FDA）的标准，FFC被发现是一种潜在的BCRP底物，因为在稳定转染鸡BCRP的MDCK细胞中，FFC的净流出比超过2.0(2.37)，而且这种流出被BCRP抑制剂（吉非替尼）完全逆转。分子对接结果表明，氟苯尼考可与同源模型鸡BCRP结合袋形成良好的相互作用。对不同年龄、不同BCRP表达水平肉鸡FFC的药代动力学研究表明，BCRP表达水平越高，FFC的曲线下面积（AUC）越低，清除率越高。此外，观察到与吉非替尼（一种BCRP抑制剂）合用后氟苯尼考的吸收更广泛。结果表明，氟苯尼考是鸡乳腺癌耐药蛋白的底物，从而影响其药代动力学行为。
Florfenicol (FFC) is a valuable synthetic fluorinated derivative of thiamphenicol widely used to treat infectious diseases in food animals. The aims of the study were to investigate whether FFC is a substrate for the breast cancer resistance protein (BCRP) and whether the transporter influences oral availability of FFC. In vitro transport assays using MDCK-chAbcg2 cells were conducted to assess chicken BCRP-mediated transport of FFC, while in vivo pharmacokinetic experiments with single or combined BCRP inhibitor gefitinib were employed to study the role of BCRP in oral FFC disposition. According to U.S. Food and Drug Administration (FDA) criteria, FFC was found to be a potential BCRP substrate due to the net efflux ratio being over 2.0 (2.37) in MDCK cells stably transfected with chicken BCRP and the efflux completely reversed by a BCRP inhibitor (Gefitinib). The molecular docking results indicated that florfenicol can form favorable interactions with the binding pocket of homology modeled chicken BCRP. Pharmacokinetic studies of FFC in different aged broilers with different expression levels of BCRP showed that higher BCRP expression would cause a lower Area Under Curve (AUC) and a higher clearance of FFC. In addition, more extensive absorption of florfenicol after the co-administration with gefitinib (a BCRP inhibitor) was observed. The overall results demonstrated that florfenicol is a substrate of the chicken breast cancer resistant protein which in turn affects its pharmacokinetic behavior.
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影响因子：
14.9
作者：
Kim S;Thiessen PA;Bolton EE;Chen J;Fu G;Gindulyte A;Han L;He J;He S;Shoemaker BA;Wang J;Yu B;Zhang J;Bryant SH
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DOI：
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