Abstract
Modulation of P-glycoprotein (P-gp, encoded by Mdr1) by xenobiotics plays central role in pharmacokinetics of various drugs. Quercetin has a potential to modulate P-gp in rodents, however, its effects on P-gp modulation in chicken are still unclear. Herein, study reports role of quercetin in modulation of P-gp expression and subsequent effects on the pharmacokinetics of enrofloxacin in broilers. Results show that P-gp expression was increased in a dose-dependent manner following exposure to quercetin in Caco-2 cells and tissues of chicken. Absorption rate constant and apparent permeability coefficient of rhodamine 123 were decreased, reflecting efflux function of P-gp in chicken intestine increased by quercetin. Quercetin altered pharmacokinetic of enrofloxacin by decreasing area under curve, peak concentration, and time to reach peak concentration and by increasing clearance rate. Molecular docking shows quercetin can form favorable interactions with binding pocket of chicken xenobiotic receptor (CXR). Results provide convincing evidence that quercetin induced P-gp expression in tissues by possible interaction with CXR, and consequently reducing bioavailability of orally administered enrofloxacin through restricting its intestinal absorption and liver/kidney clearance in broilers. The results can be further extended to guide reasonable use of quercetin to avoid drug-feed interaction occurred with co-administered enrofloxacin or other similar antimicrobials.
Highlights
Modulation of P-glycoprotein (P-gp, encoded by multidrug resistance protein 1 (Mdr1)) by xenobiotics plays central role in pharmacokinetics of various drugs
The docking scores support our assumption that quercetin may interact with the same proteins as the other P-gp inducers, and in this case, we have focused on the chicken xenophobic receptor (CXR) and chicken vitamin D receptor (CVDR) that are known to be involved in the up-regulation of P-gp expression[15,21]
As one of the ingredients in poultry feed that comes from plants, quercetin may affect the bioavailability or the withdrawal period of P-gp substrates in chickens, which is of high practical relevance from therapeutic efficacy and food safety point of the view
Summary
Modulation of P-glycoprotein (P-gp, encoded by Mdr1) by xenobiotics plays central role in pharmacokinetics of various drugs. Study reports role of quercetin in modulation of P-gp expression and subsequent effects on the pharmacokinetics of enrofloxacin in broilers. Results provide convincing evidence that quercetin induced P-gp expression in tissues by possible interaction with CXR, and reducing bioavailability of orally administered enrofloxacin through restricting its intestinal absorption and liver/kidney clearance in broilers. Quercetin is one of the flavonoids which are natural polyphenolic compounds found in numerous components of the human daily diet, including red wine, onions, apples, tea and grapefruit juice[1] It exerts a broad range of fascinating clinical properties, such as anti-inflammatory[2], antineoplastic[3], antimicrobial[4], antiallergic[5] and antiviral[6] activities. Our results indicate that quercetin could upregulate the expression and activity of the P-gp in Caco-2 cells and in different tissues of the broiler, and importantly modulate pharmacokinetics of orally administered enrofloxacin in chicken. The current results can be helpful in guiding rational use of additives and drugs in the poultry industry to avoid possible adverse effects
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