Qian M R, Wang Q Y, Yang H, Sun G Z, Ke X B, Huang L L, Gao J D, Yang J J, Yang B
State Key Laboratory Breeding Base for Zhejiang Sustainable Plant Pest Control; Institute of Quality and Standard for Agro-Products, Zhejiang Academy of Agricultural Sciences, Hangzhou, China.
Wuhan Agricultural School, Wuhan, China.
J Vet Pharmacol Ther. 2017 Dec;40(6):e30-e38. doi: 10.1111/jvp.12419. Epub 2017 Jun 1.
For most bacterial lung infections, the concentration of unbound antimicrobial agent in lung interstitial fluid has been thought to be responsible for antimicrobial efficacy. In this study, a diffusion-limited physiologically based pharmacokinetic (PBPK) model was developed to predict the pulmonary pharmacokinetics of florfenicol (FF) in pigs. The model included separate compartments corresponding to blood, diffusion-limited lung, flow-limited muscle, liver, and kidney and an extra compartment representing the remaining carcass. The absorption rate constant and renal and hepatic clearance of FF were determined in vivo. Other parameters were taken from the literature or optimized based on existing pharmacokinetic data. All mathematical operations during the development of the model were performed using acslXtreme version 3.0.2.1 (Aegis Technologies Group, Inc., Huntsville, AL, USA). The model accurately predicted the concentration-time courses of FF in lung interstitial fluid, serum, and plasma following different dosing schedules, except at the dose of 15 mg/kg. When compared with the tissue residue data, the model generally underestimated the FF concentration at the injection site, whereas it gave good predictions of FF concentrations in lung, liver, and kidney at early time points. The model predictions provide a scientific basis for the dosage regimen design of FF.
对于大多数细菌性肺部感染，人们认为肺间质液中游离抗菌剂的浓度决定了抗菌效果。在本研究中，建立了一个基于生理药代动力学（PBPK）的扩散限制模型，以预测氟苯尼考（FF）在猪体内的肺部药代动力学。该模型包括对应于血液、扩散限制的肺、血流限制的肌肉、肝脏和肾脏的独立隔室，以及一个代表其余胴体的额外隔室。在体内测定了FF的吸收速率常数以及肾脏和肝脏清除率。其他参数取自文献或根据现有药代动力学数据进行优化。在模型开发过程中的所有数学运算均使用acslXtreme 3.0.2.1版本（美国阿拉巴马州亨茨维尔市的Aegis Technologies Group公司）进行。该模型准确预测了不同给药方案后FF在肺间质液、血清和血浆中的浓度-时间过程，但15mg/kg剂量除外。与组织残留数据相比，该模型通常低估了注射部位的FF浓度，而在早期时间点对肺、肝脏和肾脏中的FF浓度给出了较好的预测。该模型预测为FF的给药方案设计提供了科学依据。
