ABC Transporters and CYP3A4 Mediate Drug Interactions between Enrofloxacin and Salinomycin Leading to Increased Risk of Drug Residues and Resistance

Enrofloxacin (ENR) is one of the most common drugs used in poultry production to treat bacterial diseases, and there is a high risk of drug interactions (DDIs) between polyether anticoccidial drugs added to poultry feed over time. This may affect the efficacy of antibiotics or lead to toxicity, posing a potential risk to the environment and food safety. This study aimed to investigate the DDI of ENR and salinomycin (SAL) in broilers and the mechanism of their DDI. We found that SAL increased the area under the curve and elimination half-life of ENR and ciprofloxacin (CIP) by 1.3 and 2.4 times, 1.2 and 2.5 times, respectively. Cytochrome 3A4 (CYP3A4), p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) were important factors for the DDI between ENR and SAL in broilers. ENR and SAL are substrates of CYP3A4, P-gp and BCRP in broilers; ENR and SAL inhibited the expression of CYP3A4 activity in a time- and concentration-dependent. Meanwhile, ENR downregulated the expression of P-gp and BCRP in a time- and concentration-dependent manner. A single oral administration of SAL inhibited CYP3A4, P-gp, and BCRP, but long-term mixed feeding upregulated the expression of CYP3A4, P-gp, and BCRP. Molecular docking revealed that ENR and SAL compete with each other for CYP3A4 to affect hepatic metabolism, and compete with ATP for P-gp and BCRP binding sites to inhibit efflux. ENR and SAL in broilers can lead to severe DDI. Drug residues and resistance following co-administration of ENR and SAL and other SAL-based drug-feed interactions warrant further study.