根据药代动力学模型估计在猪饲料中添加三聚氰胺后停药时间

实验通过建立鼠的三聚氰胺动力学模型(PBPK),拓展出猪的PBPK模型,从而确定适当的停药时间。结果表明:鼠模型低估了血浆中三聚氰胺的浓度,但更有效地估计了组织残留,而猪模型在早期测量时间点也有预测不足,但在后面的时间点上有很高的准确性。这些时间点直接关系到停药时间的预测。猪模型中,一次口服三聚氰胺浓度为3.0mg/kg和5.12mg/kg饲料后,依据肾残留量估计其停药时间分别为19.2h和20.9h;用慢性口服实验(饲料中三聚氰胺的浓度为3.0mg/kg和5.12mg/kg,2次/d,持续7d)估计停药时间分别为20h和21.3。h这种PBPK模型可以拓展到不同物种和多种饲喂模式,并为解决在偶然情况下动物饲料中出现少量污染问题而提供依据,确保食物的供给安全。     

A physiologically based pharmacokinetic model linking plasma protein binding interactions with drug disposition

Combination drug therapy increases the chance for an adverse drug reactions due to drug-drug interactions. Altered disposition for sulfamethazine (SMZ) when concurrently administered with flunixin meglumine (FLU) in swine could lead to increased tissue residues. There is a need for a pharmacokinetic modeling technique that can predict the consequences of possible drug interactions. A physiologically based pharmacokinetic model was developed that links plasma protein binding interactions to drug disposition for SMZ and FLU in swine. The model predicted a sustained decrease in total drug and a temporary increase in free drug concentration. An in vivo study confirmed the presence of a drug interaction. Neither the model nor the in vivo study revealed clinically significant changes that alter tissue disposition. This novel linkage approach has use in the prediction of the clinical impact of plasma protein binding interactions. Ultimately it could be used in the design of dosing regimens and in the protection of the food supply through prediction and minimization of tissue residues.     

Pharmacokinetic Modeling of Doxorubicin Pharmacokinetics in Dogs Deficient in ABCB1 Drug Transporters

Background: The identification of dogs defective in ATP‐binding cassette transporter B1 (ABCB1, MDR1) activity has prompted questions regarding pharmacokinetics (PK), efficacy and toxicity of ABCB1 substrates in these dogs. Hypothesis/Objectives: Dogs defective in ABCB1 activity (ABCB1_null) have doxorubicin (DOX) PK different from that of normal dogs (ABCB1_wt). Utilization of a physiologically based pharmacokinetic (PBPK) model allows computer simulation to study this polymorphism's impact on DOX PK. Animals: None. Methods: A virtual ABCB1_wt dog population was generated and DOX distribution, elimination, and metabolism simulated by PBPK modeling. An in silico population of virtual dogs was generated by Monte Carlo simulation, with variability in physiologic and biochemical parameters consistent with the dog population. This population was used in the PBPK model. The ABCB1 components of the model were inactivated to generate an ABCB1_null population and simulations repeated at multiple doses. Resulting DOX levels were used to generate PK parameters. Results: DOX exposures in the ABCB1_null population were increased in all simulated tissues including serum (24%) and gut (174%). Estimated dosages in the ABCB1_null population to approximate exposure in the ABCB1_wt population at a dose of 30 mg/m² were 24.8 ± 3.5 mg/m² for serum and 10.7 ± 5.9 mg/m² for gut. Conclusions and Clinical Importance: These results suggest that serum DOX concentrations are not indicative of tissue exposure, especially those with appreciable ABCB1 activity, and that gastrointestinal (GI) toxicosis would be dose limiting in ABCB1_null populations. Dosage reductions necessary to prevent GI toxicosis likely result in subtherapeutic concentrations, thereby reducing DOXs efficacy in ABCB1_null dogs.     

An integrated experimental and physiologically based pharmacokinetic modeling study of penicillin G in heavy sows

Penicillin G is widely used in food‐producing animals at extralabel doses and is one of the most frequently identified violative drug residues in animal‐derived food products. In this study, the plasma pharmacokinetics and tissue residue depletion of penicillin G in heavy sows after repeated intramuscular administrations at label (6.5 mg/kg) and 5 × label (32.5 mg/kg) doses were determined. Plasma, urine, and environmental samples were tested as potential antemortem markers for penicillin G residues. The collected new data and other available data from the literature were used to develop a population physiologically based pharmacokinetic (PBPK) model for penicillin G in heavy sows. The results showed that antemortem testing of urine provided potential correlation with tissue residue levels. Based on the United States Department of Agriculture Food Safety and Inspection Service action limit of 25 ng/g, the model estimated a withdrawal interval of 38 days for penicillin G in heavy sows after 3 repeated intramuscular injections at 5 × label dose. This study improves our understanding of penicillin G pharmacokinetics and tissue residue depletion in heavy sows and provides a tool to predict proper withdrawal intervals after extralabel use of penicillin G in heavy sows, thereby helping safety assessment of sow‐derived meat products.