Inhibitory Effect of Berberine on Broiler P-glycoprotein Expression and Function: In Situ and In Vitro Studies

• Published in: International journal of molecular sciences 2019-04, Vol.20 (8), p.1966
• Main Authors: Zhang, Yujuan, Guo, Li, Huang, Jinhu, Sun, Yong, He, Fang, Zloh, Mire, Wang, Liping
• Format: Article
• Language: English
• Subjects: Absorption; Activation; Adenosine triphosphate; Antimicrobial agents; Berberine; Bioavailability; Drug interaction; Efflux; Enrofloxacin; Gene expression; Glycoproteins; Intestine; Ivermectin; Jejunum; P-Glycoprotein; Perfusion; Pharmacokinetics; Small intestine; Verapamil; Veterinary medicine
• ISSN: 1422-0067; 1661-6596; 1422-0067
• 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.