Institute of Computational Comparative Medicine (ICCM), Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
Toxicol Sci. 2018 Jul 1;164(1):85-100. doi: 10.1093/toxsci/kfy067.
Penicillin remains one of the most frequently identified violative drug residues in food-producing animals. The predominant violations of penicillin were found in cull dairy cows. In the United States, procaine penicillin G is approved to be used in dairy cows through intramuscular (IM) and intramammary (IMM) administrations. Physiologically based pharmacokinetic (PBPK) models are useful tools to predict withdrawal intervals and tissue residues of drugs in food animals to ensure food safety, especially for extralabel drug use due to the scarcity of experimental data after extralabel administrations. Currently, no PBPK model is available to predict penicillin concentrations in milk. A population PBPK model with a physiologically based compartment for the mammary gland was established for penicillin G in dairy cows. The model predicted the tissue and milk residues well based on comparison with data from previous pharmacokinetic studies. The predicted milk discard interval of procaine penicillin G administered at 10 times the label dose for 3 repeated IM administrations was 182 h, and 122 h at 4 times the label dose after 3 repeated IMM infusions. Predicted results showed that even 4 times label dose did not lead to violative tissue residues in healthy dairy cows with IMM infusions. The predominant violations found in cull dairy cows may be caused by altered pharmacokinetics due to mastitis, other diseases, and/or interactions with other drugs, which have impacts on penicillin distribution and elimination. The current PBPK model can help predict milk discard interval for penicillin following extralabel use through IM and IMM administrations.
青霉素仍然是在食用动物中最常被发现的违规药物残留之一。主要的违规行为发生在淘汰奶牛身上。在美国，普鲁卡因青霉素 G 被批准通过肌肉内（IM）和乳房内（IMM）给药用于奶牛。基于生理学的药代动力学（PBPK）模型是预测药物在食用动物中停药间隔和组织残留的有用工具，以确保食品安全，特别是对于标签外使用的药物，因为标签外给药后缺乏实验数据。目前，尚无 PBPK 模型可用于预测牛奶中的青霉素浓度。建立了一个用于奶牛青霉素 G 的基于生理学的乳腺隔室的群体 PBPK 模型。该模型通过与先前药代动力学研究的数据进行比较，很好地预测了组织和牛奶残留。在重复 3 次 IM 给药 10 倍标签剂量的普鲁卡因青霉素 G 后，预测的牛奶弃置间隔为 182 小时，在重复 3 次 IMM 输注后 4 倍标签剂量时为 122 小时。预测结果表明，即使在 IMM 输注时使用 4 倍标签剂量，健康奶牛也不会导致组织残留违规。淘汰奶牛中主要的违规行为可能是由于乳腺炎、其他疾病和/或与其他药物的相互作用导致的药代动力学改变引起的，这些因素会影响青霉素的分布和消除。目前的 PBPK 模型可以帮助预测通过 IM 和 IMM 给药标签外使用青霉素的牛奶弃置间隔。
