Huang Lingli, Lin Zhoumeng, Zhou Xuan, Zhu Meiling, Gehring Ronette, Riviere Jim E, Yuan Zonghui
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.
Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2015;32(12):2002-17. doi: 10.1080/19440049.2015.1100330. Epub 2015 Nov 5.
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.
基于生理的药代动力学（PBPK）模型是预测食用动物体内兽药组织分布和消除情况的有力工具。然而，大多数模型仅模拟母体药物的药代动力学，而不考虑其代谢产物。在本研究中，开发了一种PBPK模型，用于同时描述食用动物抗菌剂喹赛多（CYA）及其标记残留1,4-双去氧喹赛多（BDCYA）在猪体内的消除情况。CYA和BDCYA子模型包括血液、肝脏、肾脏、胃肠道、肌肉、脂肪和其他器官隔室。通过实验测量了BDCYA的血浆蛋白结合程度、肾清除率和组织-血浆分配系数。该模型用连续五天经口灌胃给予CYA的猪的报道药代动力学和残留消除数据进行校准，然后外推至饲料中暴露两个月的情况。该模型用连续14天的饲料给药数据进行验证。该PBPK模型准确模拟了口服暴露和2个月饲料给药后24 - 120小时四个可食用组织中的CYA和BDCYA。在饲料给药时，早期时间点（6 - 12小时）肌肉中的CYA和肾脏中的BDCYA仅略有高估。蒙特卡罗分析表明估计的浓度分布与观测数据之间具有极好的一致性。本模型可用于食用动物中CYA和BDCYA的组织残留监测，并为开发预测食用动物中母体药物及其代谢产物残留消除的PBPK模型提供了基础。
