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

Abstract

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.

Curcumin ameliorates duodenal toxicity of AFB1 in chicken through inducing P-glycoprotein and downregulating cytochrome P450 enzymes

“…Moreover, P-gp is an important member of the ATP-binding transport family, which can pump exogenous substances out of the cell with the energy generated by the hydrolysis of ATP, thereby reducing the concentration of the drug in the cell ( Peachey et al., 2017 ). Various components in fruits and vegetables and traditional Chinese medicines in daily life can regulate the activity of P-gp, and could thereby affect the intestinal absorption of P-gp substrates ( Bhutto et al., 2018 ; Zhang et al., 2019 ). It has been reported that quercetin and rutin significantly reduce the oral bioavailability of cyclosporine through activating P-gp ( Yu et al., 2011 ).…”

Solid Lipid Nanoparticles for Duodenum Targeted Oral Delivery of Tilmicosin

“…Zhang et al [ 46 ] revealed that enrofloxacin, tilmicosin, ciprofloxacin, and ampicillin are the co-substrate of P-gp and BCRP (Breast cancer resistance protein). The Papp of enrofloxacin, tilmicosin, ciprofloxacin, and ampicillin to the MDCK-chAbcb1 cell models was obviously enhanced by co-incubation with berberine (P-gp inhibitor) [ 47 ]. Combining duodenum-targeted release with non-pharmacological activity inhibitor agents will be a potential method to improve the oral absorption of these VAs.…”

Uterine Metabolomic Analysis for the Regulation of Eggshell Calcification in Chickens

“…Notably, eggshell thickness and strength rapidly returned to normal, indicating that verapamil is metabolized in a short time. Early studies focused on the effects of verapamil on chicken biventer-cervicis muscle [ 35 ], atherosclerotic chickens [ 36 , 37 ], and shifts in drug–drug interactions when broilers were treated with the specific P-glycoprotein inhibitor verapamil [ 38 ]. It is uncommon to add verapamil to the chicken’s diet during egg production, and few studies have focused on the effects of verapamil on layers and chicken egg quality although verapamil could attenuate lipopolysaccharide [ 39 ] and colibacillosis [ 30 ] in broilers when treated with oral enrofloxacin.…”