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.     

Development of a multiroute physiologically based pharmacokinetic model for orbifloxacin in rabbits

To predict the orbifloxacin concentrations in rabbits after multiple routes of administration, a flow‐limited multiroute physiologically based pharmacokinetic (PBPK) model was developed. Three routes of administration (IV, IM, and PO) were incorporated into this model. Physiological parameters including tissue weights and blood flows through different tissues were obtained from the literature. The tissue/plasma partition coefficients (P_Xs) for noneliminating tissues were calculated according to the area method, while the P_Xs for kidney and the rest of the body compartment, together with other parameters for absorption and elimination, were optimized based on the published concentrations. The comparisons between predicted and observed orbifloxacin concentrations proved its validity, and the present model predicted available concentration data well, including those in liver, kidney, muscle, lung, heart, and plasma after oral, intravenous, or intramuscular administration. A local sensitivity analysis was also performed, which showed that the parameters for oral absorption were most influential on the orbifloxacin concentrations. This model was used to predict plasma and tissue concentrations after multiple oral or intramuscular administration. This study demonstrated the feasibility of predicting drug residues in minor species after multiple routes of administration in the extra‐label manner using the PBPK modeling.     

The construction and application of a population physiologically based pharmacokinetic model for methadone in Beagles and Greyhounds

Methadone is an opioid analgesic in veterinary and human medicine. To help develop appropriate pain management practices and to develop a quantitative model for predicting methadone dosimetry, a flow‐limited multiroute physiologically based pharmacokinetic (PBPK) model for methadone in dogs constructed with Berkeley Madonna? was developed. The model accounts for intravenous (IV), subcutaneous (SC), and oral administrations, and compartmentalizes the body into different components. This model was calibrated from plasma pharmacokinetic data after IV administration of methadone in Beagles and Greyhounds. The calibrated model was evaluated with independent data in both breeds of dogs. One advantage of this model is that most physiological parameter values for Greyhounds were taken directly from the original literature. The developed model simulates available pharmacokinetic data for plasma concentrations well for both breeds. After conducting regression analysis, all simulated datasets produced an R ² > 0.80 when compared to the measured plasma concentrations. Comparative analysis of the dosimetry of methadone between the breeds suggested that Greyhounds had ~50% lower 24‐hr area under the curve (AUC) of plasma or brain concentrations than in Beagles. Furthermore, population analysis was conducted with this study. This model can be used to predict methadone concentrations in multiple dog breeds using breed‐specific parameters.     

草原红牛IGFBP3基因多态性及与部分屠宰性状的相关性分析

以草原红牛为研究对象,采用PCR-SSCP方法检测IGFBP3基因的多态性,并将不同基因型与部分屠宰性状进行相关分析.结果表明在第2内含子发现多态性位点,有AA、AB和BB 3种基因型;测序结果显示在8 069 bp处存在C→T的碱基突变;该位点的多态性对草原红牛的眼肌面积有显著影响(P<0.05),AA型显著高于BB型(P<0.05),但与AB型之间差异不显著(P>0.05);其他屠宰性状在不同基因型间差异不显著.由此可以初步推断IGFBP3基因可能是影响草原红牛肉质性状的一个主效基因或是一个与影响肉质性状的QTL连锁的基因.