Development And Extrapolation Of A Physiologically Based Pharmacokinetic Model For Residue Depletion Of Quinocetone In Pigs

Veterinary drug residues are caused by the unreasonable use of veterinary drugs.Veterinary drug residues have bad influence on human health and ecological balance.Quinocetone(QCT),as an antimicrobial agent and growth promoting agent,is widely used in pig industry in china.The existing residue monitoring system can't prevent the violated residue of QCT in food-producing animals because of off-label use phenomenon.Meanwhile,sampling examination method may give rise to serious economic losses.Physiologically based pharmacokinetic(PBPK)model,as a scientific residue prediction method,can efficiently make up for the shortage of existing residue monitoring system.To improve the residue monitoring systems of quinoxalines and guarantee the safety of animal derived food,a PBPK model for QCT was developed to predict the residues of QCT and dideoxyquinocetone(DQCT)in edible tissues of pigs.And then the PBPK models of QCT in chicken and fish were built by cross-species extrapolation.Besides,the PBPK models of olaquindox(OLA)and mequindox(MEQ)in pigs were built by cross-compounds extrapolation.1.Development of the PBPK model for the prediction of QCT in pigsThe plasma protein binding rates of QCT and DQCT were determined by equilibrium dialysis method.The results showed that the equilibrium of the QCT and DQCT concentrations between the inside and outside of the dialysis bags were achieved after 48 h,and the measured values of QCT and DQCT were 89.71%and 89.47%(n=9).Eight pigs were used to determine the renal clearances of QCT and DQCT.The results showed that the measured values of QCT and DQCT were 0.041 and 0.104 L/h/kg(n=4).Eight pigs were used to determine the tissue/plasma partition coefficients of QCT and DQCT by steady-state administration method.The partition coefficients of QCT in liver,kidney,muscle and fat were 1.88,2.08,1.27 and 0.99(n=4).The partition coefficients of DQCT in liver,kidney,muscle and fat were 2.85,3.87,0.96 and 0.74(n=4).The physiological parameters,such as cardiac output,organ blood flow and organ volume,were obtained from the published literature.Based on the results mentioned above and pharmacokinetic profiles of QCT,a flow-limited PBPK model was developed to predict the residue depletion of QCT and DQCT in pigs.In the PBPK model,a first-order rate equation was used to describe the metabolism that QCT turned into DQCT in liver.To enhance the predictive ability of model,enterohepatic circulation was included in the model structure.The targeted adjustment and step-by-step strategies for parameter estimation were adopted in the process of model fitting.Sensitive parameters were obtained by sensitivity analysis using forward difference formula.Based on the results of sensitivity analysis,uncertainty analysis was performed by Monte Carlo simulation including 1000 iterations.Model verification was conducted by comparing model predicted value with external pharmacokinetic and residue depletion data set from the published literature.A variety of ways were taken to evaluate model predictive ability,including visual interpretation,residual analysis,regression analysis and predictions within a factor of 2 of the experimental data analysis.The results showed that most of experimental data were predicted accurately.The sensitive parameters were bioavailability,absorption rate constant,metabolic rate constant,excretion rate constant and tissue/plasma partition coefficients.Monte Carlo simulation results showed that all measured value were within the predicted range.2.Extrapolation of the PBPK model of QCT in pigsBased on the PBPK model of QCT in pigs,the PBPK models of QCT in chicken and fish were built by cross-species extrapolation;meanwhile,the PBPK models of OLA and MEQ in pig were built by cross-compounds extrapolation.Physiological parameters of chicken and fish were collected from the published literature.Compound specific parameters of OLA and MEQ were obtained from the published literature or parameter estimation based on the pharmacokinetic and residue depletion data sets.The results showed that a majority of experimental data were well predicted.Almost all the predicted data were within a factor of 2 of the experimental data.The extrapolated PBPK models were still able to predict the residues of QCT in chicken,fish and OLA,MEQ in pigs.In conclusion,a PBPK model of QCT was developed to predict the residues of QCT and DQCT for various exposure situations in edible tissues of pigs for the first time.And then the PBPK models of QCT in chicken and fish were built by cross-species extrapolation.The PBPK models of OLA and MEQ in pig were built by cross-compounds extrapolation.The results of the present study contribute to improve the residue monitoring system of quinoxalines and guarantee the safety of animal derived food.At the same time,the present study also expanded the using extent of PBPK models in veterinary drugs.