The extensive use of doxycycline in aquaculture results in drug residue violations that negatively impact human food safety. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model for doxycycline to predict drug residues and withdrawal times (WTs) in grass carp (Ctenopharyngodon idella) after daily oral administration for 3 days. Physiological parameters including cardiac output and organ weights were measured experimentally. Chemical-specific parameters were obtained from the literature or estimated by fitting to the observed data. The model properly captured the observed kinetic profiles of doxycycline in tissues (i.e., liver, kidney, muscle + skin and gill). The predicted WT in muscle + skin by Monte Carlo analysis based on sensitive parameters identified at 24 h after drug administration was 41 d, which was similar to 43 d calculated using the tolerance limit method. Sensitivity analysis identified two additional sensitive parameters at 6 weeks: intestinal transit rate constant and urinary elimination rate constant. The predicted WT in muscle + skin based on sensitive parameters identified at 6 weeks was 54 d. This model provides a useful tool to estimate tissue residues and withdrawal times for doxycycline in grass carp and also serves a foundation for extrapolation to other fish species and other tetracyclines.

中文翻译：

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多西环素的基于生理的药代动力学模型，用于预测草鱼（Ctenopharyngodon idella）中的组织残留和停药间隔。

强力霉素在水产养殖中的广泛使用导致药物残留违规，对人类食品安全产生负面影响。这项研究旨在为多西环素建立一种基于生理学的药代动力学（PBPK）模型，以预测每天口服3天后草鱼（Ctenopharyngodon idella）中的药物残留和停药时间（WTs）。生理参数包括心输出量和器官重量通过实验测量。化学特有的参数是从文献中获得的，或者是通过拟合观察到的数据来估算的。该模型正确捕获了在组织（即肝，肾，肌肉，皮肤和g）中观察到的强力霉素的动力学特征。根据药物给药后24 h识别出的敏感参数，通过蒙特卡洛分析法预测的肌肉+皮肤中的WT为41 d，这类似于使用公差极限法计算的43 d。敏感性分析在6周时确定了另外两个敏感参数：肠运输速度常数和尿液排泄速度常数。根据在6周时确定的敏感参数，肌肉+皮肤中的预计WT为54 d。该模型为估算草鱼中强力霉素的组织残留量和撤药时间提供了有用的工具，也为推断其他鱼类和其他四环素提供了基础。