Zhou Kaixiang, Liu Aimei, Ma Wenjin, Sun Lei, Mi Kun, Xu Xiangyue, Algharib Samah Attia, Xie Shuyu, Huang Lingli
National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Wuhan 430070, China.
Department of Clinical Pathology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh 13736, Egypt.
Antibiotics (Basel). 2021 Aug 8;10(8):955. doi: 10.3390/antibiotics10080955.
Enrofloxacin (ENR) granules were developed to prevent and control the infections caused by foodborne zoonotic intestinal pathogens in our previous studies. To promote the further development of ENR granules and standardize their usage in pigs, a physiologically based pharmacokinetic (PBPK) model of the ENR granule in pigs was built to determine the withdrawal time (WT) and evaluate the toxicity to pigs. Meanwhile, the population WT was determined by a Monte Carlo analysis to guarantee pork safety. The fitting results of the model showed that the tissue residual concentrations of ENR, ciprofloxacin, and ENR plus ciprofloxacin were all well predicted by the built PBPK model (R > 0.82). When comparing with the EMA's WT1.4 software method, the final WT (6 d) of the ENR granules in the population of pigs was well predicted. Moreover, by combining the cytotoxicity concentration (225.9 µg/mL) of ENR against pig hepatocytes, the orally safe dosage range (≤130 mg/kg b.w.) of the ENR granules to pigs was calculated based on the validated PBPK model. The well-predicted WTs and a few uses in animals proved that the PBPK model is a potential tool for promoting the judicious use of antimicrobial agents and evaluating the toxicity of the veterinary antimicrobial products.
在我们之前的研究中，开发了恩诺沙星（ENR）颗粒以预防和控制食源性人畜共患肠道病原体引起的感染。为了促进ENR颗粒的进一步发展并规范其在猪中的使用，建立了猪体内ENR颗粒的生理药代动力学（PBPK）模型，以确定休药期（WT）并评估对猪的毒性。同时，通过蒙特卡洛分析确定群体休药期，以确保猪肉安全。模型拟合结果表明，所建立的PBPK模型能很好地预测ENR、环丙沙星以及ENR加环丙沙星的组织残留浓度（R>0.82）。与EMA的WT1.4软件方法相比，该模型能很好地预测猪群体中ENR颗粒的最终休药期（6天）。此外，结合ENR对猪肝细胞的细胞毒性浓度（225.9µg/mL），基于验证后的PBPK模型计算出ENR颗粒对猪的口服安全剂量范围（≤130mg/kg体重）。预测良好的休药期以及在动物中的少量应用证明，PBPK模型是促进抗菌药物合理使用和评估兽用抗菌产品毒性的潜在工具。
