Transporter-Mediated Modulation of Veterinary Drug Residues in Milk: A One Health Computational Toxicology Framework

Veterinary drug residues in milk represent a critical interface between animal health, food safety, and public health, particularly when co-administered pharmaceuticals influence residue dynamics. Current residue risk assessment frameworks are primarily based on single-compound pharmacokinetics and do not account for transporter-mediated drug–drug interactions that may alter the secretion of xenobiotics into milk. In this study, a One Health-oriented computational toxicology framework was developed to investigate the potential modulation of marbofloxacin residues by ivermectin via the ABCG2/BCRP efflux transporter. An ovine ABCG2 homology model was constructed and evaluated using established structural quality metrics. Molecular docking and molecular dynamics simulations were employed to assess binding affinity, interaction stability, and potential inhibitory effects of ivermectin on transporter function in comparison to marbofloxacin. The study combined homology modelling, molecular docking, and molecular dynamics simulations to investigate the interaction of marbofloxacin and ivermectin with the ovine ABCG2/BCRP transporter and to evaluate potential effects on transporter-mediated drug secretion. The results indicate that ivermectin exhibits stable binding within the transporter cavity and interacts with key functional residues, suggesting a potential inhibitory effect on substrate efflux. This interaction may influence the secretion of marbofloxacin into milk and modify the kinetics of residue depletion. These findings highlight the importance of considering transporter-level interactions in veterinary drug residue evaluation. The proposed framework supports integrating in silico approaches into predictive residue toxicology and provides a mechanistic basis for improving risk assessment strategies. From a One Health perspective, this approach contributes to a more comprehensive understanding of factors affecting food safety, antimicrobial exposure, and regulatory decision-making related to maximum residue limits and withdrawal periods.