Lin Zhoumeng, Cuneo Matthew, Rowe Joan D, Li Mengjie, Tell Lisa A, Allison Shayna, Carlson Jan, Riviere Jim E, Gehring Ronette
Institute of Computational Comparative Medicine (ICCM), Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Avenue, P200 Mosier Hall, Manhattan, KS, 66506-5802, USA.
Department of Population, Health and Reproduction, College of Agricultural and Environmental Sciences, University of California, Davis, CA, 95616, USA.
BMC Vet Res. 2016 Nov 18;12(1):258. doi: 10.1186/s12917-016-0884-4.
Extra-label use of tulathromycin in lactating goats is common and may cause violative residues in milk. The objective of this study was to develop a nonlinear mixed-effects pharmacokinetic (NLME-PK) model to estimate tulathromycin depletion in plasma and milk of lactating goats. Eight lactating goats received two subcutaneous injections of 2.5 mg/kg tulathromycin 7 days apart; blood and milk samples were analyzed for concentrations of tulathromycin and the common fragment of tulathromycin (i.e., the marker residue CP-60,300), respectively, using liquid chromatography mass spectrometry. Based on these new data and related literature data, a NLME-PK compartmental model with first-order absorption and elimination was used to model plasma concentrations and cumulative excreted amount in milk. Monte Carlo simulations with 100 replicates were performed to predict the time when the upper limit of the 95% confidence interval of milk concentrations was below the tolerance.
All animals were healthy throughout the study with normal appetite and milk production levels, and with mild-moderate injection-site reactions that diminished by the end of the study. The measured data showed that milk concentrations of the marker residue of tulathromycin were below the limit of detection (LOD = 1.8 ng/ml) 39 days after the second injection. A 2-compartment model with milk as an excretory compartment best described tulathromycin plasma and CP-60,300 milk pharmacokinetic data. The model-predicted data correlated with the measured data very well. The NLME-PK model estimated that tulathromycin plasma concentrations were below LOD (1.2 ng/ml) 43 days after a single injection, and 62 days after the second injection with a 95% confidence. These estimated times are much longer than the current meat withdrawal time recommendation of 18 days for tulathromycin in non-lactating cattle.
The results suggest that twice subcutaneous injections of 2.5 mg/kg tulathromycin are a clinically safe extra-label alternative approach for treating pulmonary infections in lactating goats, but a prolonged withdrawal time of at least 39 days after the second injection should be considered to prevent violative residues in milk and any dairy goat being used for meat should have an extended meat withdrawal time.
在泌乳山羊中，土拉霉素的超说明书用药很常见，可能会导致牛奶中出现违规残留。本研究的目的是建立一个非线性混合效应药代动力学（NLME-PK）模型，以估计土拉霉素在泌乳山羊血浆和牛奶中的消除情况。八只泌乳山羊每隔7天接受两次2.5毫克/千克土拉霉素的皮下注射；分别使用液相色谱质谱法分析血液和牛奶样本中土拉霉素及其常见片段（即标记残留物CP-60,300）的浓度。基于这些新数据和相关文献数据，使用具有一级吸收和消除的NLME-PK房室模型对血浆浓度和牛奶中的累积排泄量进行建模。进行了100次重复的蒙特卡洛模拟，以预测牛奶浓度95%置信区间上限低于耐受限度的时间。
在整个研究过程中，所有动物均健康，食欲和产奶水平正常，注射部位有轻度至中度反应，在研究结束时减轻。实测数据表明，第二次注射后39天，土拉霉素标记残留物的牛奶浓度低于检测限（LOD = 1.8纳克/毫升）。以牛奶作为排泄房室的二房室模型最能描述土拉霉素血浆和CP-60,300牛奶药代动力学数据。模型预测数据与实测数据相关性很好。NLME-PK模型估计，单次注射后43天，土拉霉素血浆浓度低于检测限（1.2纳克/毫升），第二次注射后62天，95%置信度下低于检测限。这些估计时间比目前非泌乳牛中土拉霉素18天的肉类停药时间建议长得多。
结果表明，两次皮下注射2.5毫克/千克土拉霉素是治疗泌乳山羊肺部感染的一种临床上安全的超说明书替代方法，但应考虑在第二次注射后至少延长39天的停药时间，以防止牛奶中出现违规残留，任何用于肉类生产的奶山羊都应延长肉类停药时间。
