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.

Human Food Safety Implications of Variation in Food Animal Drug Metabolism

“…This modeling strategy represents a significant advance in this field because published PBPK models for veterinary drugs all focus on a single drug or one species181920212223. These available models have different model structures that prevent direct comparisons of the pharmacokinetics of different drugs across species.…”

“…Physiological parameters for cattle and swine were obtained from the literature182022 and are provided in Supplementary Table 2. Initial values for partition coefficients were obtained from earlier PBPK models for flunixin and sulfamethazine2022, or calculated using tissue:plasma AUC (area under the concentration curve) ratio method based on pharmacokinetic data in cattle for enrofloxacin29, or based on the reported tissue penetration factors for ceftiofur27.…”

Development of a multiroute physiologically based pharmacokinetic model for orbifloxacin in rabbits

“…In recent years, there has been an increase in the applications of physiologically based pharmacokinetic (PBPK) models to predict veterinary drug residues (Huang et al., ; Li, Gehring, Riviere, & Lin, ; Yang, Huang, et al., ; Yang et al., ; Yang, Sun, Liu, & Zeng, ; Yang, Sun, et al., ; Yang et al., ; Zeng et al., ). Compared with the traditional monitoring method after animal slaughter, the PBPK model is based on mass‐balance equations defined by physiological mechanisms, and it is predictive in nature and allows for the use of in vitro mechanistic data and population variability data to predict the distribution of drug in animals (Lin, Gehring, Mochel, Lave, & Riviere, ).…”

An integrated experimental and physiologically based pharmacokinetic modeling study of penicillin G in heavy sows

“…In the last decade, PBPK modeling has been widely used in the area of veterinary medicine, from the prediction of drug tissue residues (Huang et al, ; Leavens et al, ; Yang et al, ), estimating the withdrawal time (Buur, Baynes, Smith, & Riviere, ; Yang, Huang, et al, ; Yang, Zhou, et al, ), to facilitating the food safety assessment (Henri, Carrez, Meda, Laurentie, & Sanders, ; Lin, Gehring, Mochel, Lavé, & Riviere, ; Yang, Huang, et al, ; Yang, Zhou, et al, ). In this study, a PBPK model was established for heavy sows based on a previous generic PBPK model for swine and cattle (Li et al, ).…”