MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
Faculty of Pharmacy, University Business Academy, Trg mladenaca 5, 21000 Novi Sad, Serbia.
Int J Mol Sci. 2019 Apr 22;20(8):1966. doi: 10.3390/ijms20081966.
Overcoming P-glycoprotein (P-gp) efflux is a strategy to improve the absorption and pharmacokinetics of its substrate drugs. Berberine inhibits P-gp and thereby increases the bioavailability of the P-gp substrate digoxin in rodents. However, the effects of berberine on P-gp in chickens are still unclear. Here, we studied the role of berberine in modulating broilers P-gp expression and function through both in situ and in vitro models. In addition, molecular docking was applied to analyze the interactions of berberine with P-gp as well as with chicken xenobiotic receptor (CXR). The results showed that the mRNA expression levels of chicken P-gp and CXR decreased in the ileum following exposure to berberine. The absorption rate constant of rhodamine 123 increased after berberine treatment, as detected using an in situ single-pass intestinal perfusion model. Efflux ratios of P-gp substrates (tilmicosin, ciprofloxacin, clindamycin, ampicillin, and enrofloxacin) decreased and the apparent permeability coefficients increased after co-incubation with berberine in MDCK-chAbcb1 cell models. Bidirectional assay results showed that berberine could be transported by chicken P-gp with a transport ratio of 4.20, and this was attenuated by verapamil (an inhibitor of P-gp), which resulted in a ratio of 1.13. Molecular docking revealed that berberine could form favorable interactions with the binding pockets of both CXR and P-gp, with docking scores of -7.8 and -9.5 kcal/mol, respectively. These results indicate that berberine is a substrate of chicken P-gp and down-regulates P-gp expression in chicken tissues, thereby increasing the absorption of P-gp substrates. Our findings suggest that berberine increases the bioavailability of other drugs and that drug-drug interactions should be considered when it is co-administered with other P-gp substrates with narrow therapeutic windows.
克服 P 糖蛋白（P-gp）外排是提高其底物药物吸收和药代动力学的一种策略。小檗碱抑制 P-gp，从而增加 P-gp 底物地高辛在啮齿动物中的生物利用度。然而，小檗碱对鸡 P-gp 的影响尚不清楚。在这里，我们通过原位和体外模型研究了小檗碱调节肉鸡 P-gp 表达和功能的作用。此外，还应用分子对接分析了小檗碱与 P-gp 以及鸡外源性受体（CXR）的相互作用。结果表明，小檗碱暴露后鸡 P-gp 和 CXR 的 mRNA 表达水平在回肠中降低。在用原位单次通过肠灌流模型检测时，小檗碱处理后 rhodamine 123 的吸收速率常数增加。在 MDCK-chAbcb1 细胞模型中与小檗碱共孵育后，P-gp 底物（替米考星、环丙沙星、克林霉素、氨苄西林和恩诺沙星）的外排比降低，表观渗透系数增加。双向测定结果表明，小檗碱可被鸡 P-gp 转运，转运比为 4.20，用 P-gp 抑制剂维拉帕米（verapamil）处理后转运比为 1.13。分子对接显示小檗碱可与 CXR 和 P-gp 的结合口袋形成有利相互作用，对接评分分别为-7.8 和-9.5 kcal/mol。这些结果表明小檗碱是鸡 P-gp 的底物，并下调鸡组织中 P-gp 的表达，从而增加 P-gp 底物的吸收。我们的研究结果表明，小檗碱增加了其他药物的生物利用度，当与其他具有狭窄治疗窗的 P-gp 底物同时给药时，应考虑药物相互作用。
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