Understanding the pharmacokinetics of intra-mammary antibiotics is important for the prediction of drug residues in milk and for the design of optimal dosage regimens. Unfortunately, compartmental pharmacokinetic models are not valid for this unique system. A minimal physiologically based pharmacokinetic model is presented incorporating the physiology of milk secretion, drug administration at the quarter level, drug absorption and dispersion, drug retention during the inter-milking interval and episodic drug elimination at milking. The primary objective of the study was the development and exploration of a model for major factors controlling drug concentration in milk, rather than generation of rigorously predictive pharmaco-statistical models for any particular drug. This model was implemented in a two-stage approach, using published concentration data for penicillin, cefuroxime, cephapirin and desacetyl-cephapirin in milk of healthy cows. Model simulations evaluated sensitivity and developed predictions of drug residues. The model successfully predicted both drug concentrations and drug residues in milk. The postmilking residual milk volume did not adequately explain antibiotic pharmacokinetics, requiring additional considerations for drug retention. Local sensitivity analysis indicated that increasing the number of quarters treated, the dosage, or the duration of the inter-milking interval prolonged both the persistence of drug residues and the duration that antibiotic concentration exceeded typical minimum inhibitory concentrations. The model was flexible across different beta-lactam drugs as a general description of intra-mammary pharmacokinetics. This model is suitable for the design and analysis of dosage regimens, and could be applied for the prediction of withholding periods when these antibiotic preparations are used off-label. The final model indicates that explicit consideration of the milking regimen is fundamental to the design and interpretation of pharmacokinetic studies of antibiotics in bovine milk.

中文翻译：

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乳牛乳内给药后三种β-内酰胺类抗生素药代动力学的基于生理学的建模。

了解乳内抗生素的药代动力学对于预测牛奶中的药物残留量和设计最佳剂量方案非常重要。不幸的是，隔室药代动力学模型对于这种独特的系统无效。提出了一个基于生理的最小药代动力学模型，该模型结合了乳汁分泌，四分之一水平的药物给药，药物吸收和分散，中间挤奶间隔期间的药物保留以及挤奶时的偶发性药物消除的生理机制。该研究的主要目的是开发和探索控制牛奶中药物浓度的主要因素模型，而不是针对任何特定药物生成严格预测的药物统计学模型。该模型采用两步法实施，使用已发表的健康奶牛牛奶中的青霉素，头孢呋辛，头孢氨苄和去乙酰头孢菌素浓度数据。模型仿真评估了灵敏度并开发了药物残留预测。该模型成功预测了牛奶中的药物浓度和药物残留。挤奶后的残留牛奶量不足以解释抗生素的药代动力学，需要对药物的保留进行其他考虑。局部敏感性分析表明，增加治疗的季度数，剂量或中间挤奶间隔的持续时间既延长了药物残留的持续时间，又延长了抗生素浓度超过典型最低抑菌浓度的持续时间。该模型在不同的β-内酰胺类药物之间具有灵活性，可作为乳内药代动力学的一般描述。该模型适用于剂量方案的设计和分析，可用于非标明使用这些抗生素制剂时的扣留期预测。最终模型表明，明确考虑挤奶方案是设计和解释牛乳中抗生素药代动力学研究的基础。