Potential pharmacokinetic effect of rifampicin on enrofloxacin in broilers: Roles of P-glycoprotein and BCRP induction by rifampicin
Potential pharmacokinetic effect of rifampicin on enrofloxacin in broilers: Roles of P-glycoprotein and BCRP induction by rifampicin
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DOI：
10.3382/ps/pew148
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发表时间：
2016-09-01
期刊：
影响因子：
4.4
通讯作者：
Wang, Liping
中科院分区：
文献类型：
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作者：
Guo, Mengjie;Dai, Xiaohua;Wang, Liping
P-糖蛋白（P-gp，编码基因Abcb 1）和乳腺癌耐药蛋白（BCRP，编码基因Abcg 2）是在调节人类和啮齿动物口服药物生物利用度中起主要作用的转运蛋白。已有研究表明，利福平是啮齿类动物中P-gp的典型诱导剂，它通过激活核受体来诱导P-gp。然而，其对Abcb 1，Abcg 2，CYP 3A和鸡异生素敏感孤儿核受体（CXR）mRNA表达的影响知之甚少。本研究探讨了利福平对肉鸡体内Abcb 1、Abcg 2、CYP 3A 37、CXR mRNA表达的影响及其对恩诺沙星药代动力学的影响。利福平处理后，肝脏（Abcg 2除外）、肾脏、空肠和回肠中Abcb 1、Abcg 2、CYP 3A 37和CXR的mRNA水平均显著升高（P < 0.05），而十二指肠中Abcb 1、Abcg 2、CYP 3A 37和CXR的mRNA水平无显著变化（P > 0.05）。进一步分析发现，肝、肾、空肠和回肠中Abcb 1、Abcg 2和CYP 3A 37表达水平的变化趋势与CXR mRNA表达水平显著相关。与利福平同时给药显著改变了恩诺沙星口服给药的药代动力学行为，显示出明显降低的AUC（0-az）、AUC（0-t）和C-max以及延长的T-max。利福平使恩诺沙星的生物利用度从72.5%下降到24.8%。然而，利福平并没有显着改变恩诺沙星静脉给药后的药代动力学。结果表明，利福平可上调肠道内P-gp和BCRP的水平，提示P-gp和BCRP通过限制肠道对恩诺沙星的吸收而影响恩诺沙星在肉鸡体内的药代动力学行为。
P-glycoprotein (P-gp, encoding gene Abcb1) and Breast Cancer Resistance Protein (BCRP, encoding gene Abcg2) are transport proteins that play a major role in modulating the bioavailability of oral drugs in humans and rodents. It has been shown that rifampicin is the typical inducer of P-gp in rodents by activating the nuclear receptor. However, its effect on Abcb1, Abcg2, CYP3A, and chicken xenobiotic-sensing orphan nuclear receptor (CXR) mRNA expression in broilers is poorly understood. This study explored the effect of rifampicin on mRNA expression of Abcb1, Abcg2, CYP3A37, CXR as well as its effect on the pharmacokinetics of enrofloxacin in broilers. The mRNA levels of Abcb1, Abcg2, CYP3A37, and CXR were significantly increased in the liver (except Abcg2), kidney, jejunum, and ileum (P < 0.05) but not significantly changed in the duodenum (P > 0.05) after treated with rifampicin. Further analysis revealed that the variation tendencies of Abcb1, Abcg2, and CYP3A37 expression levels were significantly correlated with CXR mRNA expression levels in liver, kidney, jejunum, and ileum. Coadministration of rifampicin significantly changed the pharmacokinetic behavior of enrofloxacin orally administered by showing clearly lower AUC(0-az), AUC(0-t), and C-max as well as longer T-max. The bioavailability of orally administered enrofloxacin was decreased from 72.5% to 24.8% by rifampicin. However, rifampicin did not significantly change the pharmacokinetics of enrofloxacin following intravenous administration. Our study shows that rifampicin up-regulated the small intestinal level of P-gp and BCRP and suggests that P-gp and BCRP are key factors that affected pharmacokinetic behavior of orally administered enrofloxacin by limiting its absorption from the intestine in broilers.