title: Estimation of residue depletion of cyadox and its marker residue in edible tissues of pigs using physiologically based pharmacokinetic modelling.
abstract: Physiologically based pharmacokinetic (PBPK) models are powerful tools to predict tissue distribution and depletion of veterinary drugs in food animals. However, most models only simulate the pharmacokinetics of the parent drug without considering their metabolites. In this study, a PBPK model was developed to simultaneously describe the depletion in pigs of the food animal antimicrobial agent cyadox (CYA), and its marker residue 1,4-bisdesoxycyadox (BDCYA). The CYA and BDCYA sub-models included blood, liver, kidney, gastrointestinal tract, muscle, fat and other organ compartments. Extent of plasma-protein binding, renal clearance and tissue-plasma partition coefficients of BDCYA were measured experimentally. The model was calibrated with the reported pharmacokinetic and residue depletion data from pigs dosed by oral gavage with CYA for five consecutive days, and then extrapolated to exposure in feed for two months. The model was validated with 14 consecutive day feed administration data. This PBPK model accurately simulated CYA and BDCYA in four edible tissues at 24-120 h after both oral exposure and 2-month feed administration. There was only slight overestimation of CYA in muscle and BDCYA in kidney at earlier time points (6-12 h) when dosed in feed. Monte Carlo analysis revealed excellent agreement between the estimated concentration distributions and observed data. The present model could be used for tissue residue monitoring of CYA and BDCYA in food animals, and provides a foundation for developing PBPK models to predict residue depletion of both parent drugs and their metabolites in food animals.
authors.affiliation: a MOA Laboratory of Risk Assessment for Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University , Wuhan , 430070 , China.|b Institute of Computational Comparative Medicine (ICCM), College of Veterinary Medicine , Kansas State University , Manhattan , KS 66506 , USA.|c Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety , Huazhong Agricultural University , Wuhan , 430070 , China.
authors.forename: Lingli
authors.initials: L
authors.lastname: Huang
authors.affiliation: d National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University , Wuhan , 430070 , China.
authors.forename: Zhoumeng
authors.initials: Z
authors.lastname: Lin
authors.affiliation: d National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University , Wuhan , 430070 , China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: d National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University , Wuhan , 430070 , China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Zhu
authors.affiliation: b Institute of Computational Comparative Medicine (ICCM), College of Veterinary Medicine , Kansas State University , Manhattan , KS 66506 , USA.
authors.forename: Ronette
authors.initials: R
authors.lastname: Gehring
authors.affiliation: b Institute of Computational Comparative Medicine (ICCM), College of Veterinary Medicine , Kansas State University , Manhattan , KS 66506 , USA.
authors.forename: Jim E
authors.initials: JE
authors.lastname: Riviere
authors.affiliation: a MOA Laboratory of Risk Assessment for Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University , Wuhan , 430070 , China.|c Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety , Huazhong Agricultural University , Wuhan , 430070 , China.|d National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University , Wuhan , 430070 , China.
authors.forename: Zonghui
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000273:Adipose Tissue / Q000737:chemistry / Q000378:metabolism; D000821:Animal Feed / Q000032:analysis; D000818:Animals; D000890:Anti-Infective Agents / Q000302:isolation & purification* / Q000378:metabolism / Q000493:pharmacokinetics; D001711:Biotransformation; D002853:Chromatography, Liquid; D004350:Drug Residues / Q000302:isolation & purification* / Q000378:metabolism; D005504:Food Analysis / Q000379:methods; D007668:Kidney / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D015233:Models, Statistical; D009010:Monte Carlo Method; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism; D011810:Quinoxalines / Q000302:isolation & purification / Q000378:metabolism / Q000493:pharmacokinetics; D013552:Swine; D053719:Tandem Mass Spectrometry; D019155:Veterinary Drugs / Q000302:isolation & purification* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D000890:Anti-Infective Agents; D011810:Quinoxalines; D019155:Veterinary Drugs; C020728:cyadox
keywords: 1,4-bisdesoxycyadox; Monte Carlo analysis; PBPK modelling; cyadox; residue prediction; sensitivity analysis; tissue depletion