Potential Pharmacokinetic Effect of Chicken Xenobiotic Receptor Activator on Sulfadiazine: Involvement of P-glycoprotein Induction.
Potential Pharmacokinetic Effect of Chicken Xenobiotic Receptor Activator on Sulfadiazine: Involvement of P-glycoprotein Induction.
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DOI：
10.3390/antibiotics11081005
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发表时间：
2022-07-26
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影响因子：
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药代动力学药物相互作用的研究强调了P-糖蛋白（P-gp）的重要性，因为它参与底物药物转运。本研究旨在探讨鸡异生素受体（CXR）对P-gp的调节作用及其对P-gp底物磺胺嘧啶药代动力学的影响。本研究以CXR的原型靶基因ALAS 1和CYP 2C 45作为CXR激活的阳性指标。结果显示，当暴露于CXR激活剂甲吡酮时，ABCB 1基因表达上调，转运蛋白活性增加。利用异位表达技术和RNA干扰来操纵细胞CXR状态，我们证实ABCB 1基因调控依赖于CXR。体内实验表明，甲吡酮诱导ABCB 1在肝脏，肾脏，十二指肠，空肠和回肠的鸡。此外，甲吡酮显著改变了口服磺胺嘧啶的药代动力学行为，（8.01 vs. 9.61 μg/mL，p < 0.05）和AUC 0-t（31.46 vs. 45.59 h·mg/L，p < 0.01），以及较高的T1/2λ（2.42 vs.1.67 h，p < 0.05）、Cl/F（0.62 vs.0.43 L/h/kg，p < 0.01）和Vz/F（2.16 vs.1.03 L/kg，p < 0.01）。总之，我们的数据表明，CXR参与P-gp的调节，因此，CXR激活剂可以影响，至少部分影响口服磺胺嘧啶的药代动力学行为。
Studies on pharmacokinetic drug–drug interactions have highlighted the importance of P-glycoprotein (P-gp) because of its involvement in substrate drug transport. This study aimed to investigate the role of chicken xenobiotic receptor (CXR) in the regulation of P-gp and its influences on pharmacokinetics of P-gp substrate sulfadiazine. ALAS1 and CYP2C45, the prototypical target genes of CXR, were used as a positive indicator for CXR activation in this study. Results show that ABCB1 gene expression was upregulated, and transporter activity was increased when exposed to the CXR activator metyrapone. Using ectopic expression techniques and RNA interference to manipulate the cellular CXR status, we confirmed that ABCB1 gene regulation depends on CXR. In vivo experiments showed that metyrapone induced ABCB1 in the liver, kidney, duodenum, jejunum and ileum of chickens. In addition, metyrapone significantly changed the pharmacokinetic behavior of orally administered sulfadiazine, with a Cmax (8.01 vs. 9.61 μg/mL, p < 0.05) and AUC0-t (31.46 vs. 45.59 h·mg/L, p < 0.01), as well as a higher T1/2λ (2.42 vs.1.67 h, p < 0.05), Cl/F (0.62 vs. 0.43 L/h/kg, p < 0.01) and Vz/F (2.16 vs.1.03 L/kg, p < 0.01). Together, our data suggest that CXR is involved in the regulation of P-gp, and, consequently, the CXR activator can affect, at least in part, the pharmacokinetic behavior of orally administered sulfadiazine.
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DOI：
10.1292/jvms.16-0315
发表时间：
2017-02-14
期刊：
The Journal of veterinary medical science
影响因子：
--
作者：
Ogushi N;Sasaki K;Shimoda M
通讯作者：
Shimoda M
影响因子：
4.8
作者：
Handschin, C;Meyer, UA
通讯作者：
Meyer, UA
DOI：
10.1007/s13318-021-00744-7
发表时间：
2021-12-22
影响因子：
1.9
作者：
Saib, Sonia;Hodin, Sophie;Delavenne, Xavier
通讯作者：
Delavenne, Xavier
影响因子：
7.2
作者：
Taha, Maie S.;Nocera, Angela;Bleier, Benjamin S.
通讯作者：
Bleier, Benjamin S.
影响因子：
4.4
作者：
Guo, Mengjie;Dai, Xiaohua;Wang, Liping
通讯作者：
Wang, Liping