title: Physiologically based pharmacokinetic model for quinocetone in pigs and extrapolation to mequindox.
abstract: Physiologically based pharmacokinetic (PBPK) models are scientific methods used to predict veterinary drug residues that may occur in food-producing animals, and which have powerful extrapolation ability. Quinocetone (QCT) and mequindox (MEQ) are widely used in China for the prevention of bacterial infections and promoting animal growth, but their abuse causes a potential threat to human health. In this study, a flow-limited PBPK model was developed to simulate simultaneously residue depletion of QCT and its marker residue dideoxyquinocetone (DQCT) in pigs. The model included compartments for blood, liver, kidney, muscle and fat and an extra compartment representing the other tissues. Physiological parameters were obtained from the literature. Plasma protein binding rates, renal clearances and tissue/plasma partition coefficients were determined by in vitro and in vivo experiments. The model was calibrated and validated with several pharmacokinetic and residue-depletion datasets from the literature. Sensitivity analysis and Monte Carlo simulations were incorporated into the PBPK model to estimate individual variation of residual concentrations. The PBPK model for MEQ, the congener compound of QCT, was built through cross-compound extrapolation based on the model for QCT. The QCT model accurately predicted the concentrations of QCT and DQCT in various tissues at most time points, especially the later time points. Correlation coefficients between predicted and measured values for all tissues were greater than 0.9. Monte Carlo simulations showed excellent consistency between estimated concentration distributions and measured data points. The extrapolation model also showed good predictive power. The present models contribute to improve the residue monitoring systems of QCT and MEQ, and provide evidence of the usefulness of PBPK model extrapolation for the same kinds of compounds.
authors.affiliation: a MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products , Huazhong Agricultural University , Wuhan , China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: a MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products , Huazhong Agricultural University , Wuhan , China.|b National Reference Laboratory of Veterinary Drug Residues (HZAU) and MOA Key Laboratory for Detection of Veterinary Drug Residues , Huazhong Agricultural University , Wuhan , China.
authors.forename: Lingli
authors.initials: L
authors.lastname: Huang
authors.affiliation: b National Reference Laboratory of Veterinary Drug Residues (HZAU) and MOA Key Laboratory for Detection of Veterinary Drug Residues , Huazhong Agricultural University , Wuhan , China.
authors.forename: Yamei
authors.initials: Y
authors.lastname: Xu
authors.affiliation: b National Reference Laboratory of Veterinary Drug Residues (HZAU) and MOA Key Laboratory for Detection of Veterinary Drug Residues , Huazhong Agricultural University , Wuhan , China.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Xie
authors.affiliation: b National Reference Laboratory of Veterinary Drug Residues (HZAU) and MOA Key Laboratory for Detection of Veterinary Drug Residues , Huazhong Agricultural University , Wuhan , China.
authors.forename: Yuanhu
authors.initials: Y
authors.lastname: Pan
authors.affiliation: b National Reference Laboratory of Veterinary Drug Residues (HZAU) and MOA Key Laboratory for Detection of Veterinary Drug Residues , Huazhong Agricultural University , Wuhan , China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Chen
authors.affiliation: b National Reference Laboratory of Veterinary Drug Residues (HZAU) and MOA Key Laboratory for Detection of Veterinary Drug Residues , Huazhong Agricultural University , Wuhan , China.
authors.forename: Zhenli
authors.initials: Z
authors.lastname: Liu
authors.affiliation: a MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products , Huazhong Agricultural University , Wuhan , China.|b National Reference Laboratory of Veterinary Drug Residues (HZAU) and MOA Key Laboratory for Detection of Veterinary Drug Residues , Huazhong Agricultural University , Wuhan , China.
authors.forename: Zonghui
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000818:Animals; D004350:Drug Residues / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D008954:Models, Biological; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D011810:Quinoxalines / Q000032:analysis / Q000378:metabolism / Q000493:pharmacokinetics*; D013552:Swine / Q000378:metabolism*
chemical_list: C545385:Mequindox; D011810:Quinoxalines; C502851:quinocetone
keywords: Monte Carlo analysis; PBPK model; cross-compound extrapolation; mequindox; quinocetone; residue prediction