Plasma pharmacokinetics and milk residues of flunixin and 5-hydroxy flunixin following different routes of administration in dairy cattle.
Plasma pharmacokinetics and milk residues of flunixin and 5-hydroxy flunixin following different routes of administration in dairy cattle.
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DOI：
10.3168/jds.2012-5754
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发表时间：
2012-12
影响因子：
3.5
通讯作者：
L. Kissell;Geof W. Smith;T. Leavens;R. E. Baynes;Huali Wu;Jim E. Riviere
中科院分区：
文献类型：
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作者：
L. Kissell;Geof W. Smith;T. Leavens;R. E. Baynes;Huali Wu;Jim E. Riviere
本研究的目的是确定氟尼新（FLU）和5-羟基氟尼新（5OH）在肌肉注射和皮下注射与静脉注射后的血浆药代动力学和乳消除是否不同。选取12头泌乳荷斯坦奶牛进行随机交叉设计研究。按产奶量（30 kg /d）分为2组。通过静脉、肌肉和皮下注射，每隔12小时给牛注射2剂1.1mg /kg的流感病毒。给药途径之间的洗脱期为7d。在流感给药前和首次给药后36小时的不同时间点从颈静脉采集血样。在流感给药前采集复合牛奶样本，在流感首次给药后5天内每天两次采集复合牛奶样本。采用超高效液相色谱-质谱法对样品进行分析。对于流感血浆样本，观察到不同给药途径的终末半衰期的差异。静脉注射、肌肉注射和皮下注射的流感的调和平均终末半衰期分别为3.42、4.48和5.39小时。肌内和皮下给药后的平均生物利用度分别为84.5%和104.2%。最后一次给药后5OH乳浓度随时间的降低用非线性混合效应建模方法分析，表明给药途径和产奶量都是显著的协变量。并比较各给药途径在各时间点大于容许限度的乳样数，有无统计学意义。第一次给药48小时后，所有静脉注射奶牛的5OH乳浓度均未检测到；然而，一头肌肉注射和一头皮下注射的奶牛浓度可测量。在停药36 h时，这些奶牛的5OH浓度高于耐受限值。美国农业部食品安全检验局在扑杀奶牛中发现的大量流感残留物可能与未经批准的给药途径有关。经批准（静脉注射）途径感染流感的牛始终在批准的停药时间之前消除药物；然而，肌肉注射或皮下给药后，残留可以持续超过这些批准的时间。每天产奶量低于20公斤的奶牛对流感病毒的清除能力发生了变化，这也可能导致流感病毒残留超标。
The objective of this study was to determine if the plasma pharmacokinetics and milk elimination of flunixin (FLU) and 5-hydroxy flunixin (5OH) differ following intramuscular and subcutaneous injection of FLU compared with intravenous injection. Twelve lactating Holstein cows were used in a randomized crossover design study. Cows were organized into 2 groups based on milk production (30 kg of milk/d). All cattle were administered 2 doses of 1.1mg of FLU/kg at 12-h intervals by intravenous, intramuscular, and subcutaneous injections. The washout period between routes of administration was 7d. Blood samples were collected from the jugular vein before FLU administration and at various time points up to 36 h after the first dose of FLU. Composite milk samples were collected before FLU administration and twice daily for 5d after the first dose of FLU. Samples were analyzed by ultra-HPLC with mass spectrometric detection. For FLU plasma samples, a difference in terminal half-life was observed among routes of administration. Harmonic mean terminal half-lives for FLU were 3.42, 4.48, and 5.39 h for intravenous, intramuscular, and subcutaneous injection, respectively. The mean bioavailability following intramuscular and subcutaneous dosing was 84.5 and 104.2%, respectively. The decrease in 5OH milk concentration versus time after last dose was analyzed with the nonlinear mixed effects modeling approach and indicated that both the route of administration and rate of milk production were significant covariates. The number of milk samples greater than the tolerance limit for each route of administration was also compared at each time point for statistical significance. Forty-eight hours after the first dose, 5OH milk concentrations were undetectable in all intravenously injected cows; however, one intramuscularly injected and one subcutaneously injected cow had measurable concentrations. These cows had 5OH concentrations above the tolerance limit at the 36-h withdrawal time. The high number of FLU residues identified in cull dairy cows by the United States Department of Agriculture Food Safety Inspection Service is likely related to administration of the drug by an unapproved route. Cattle that received FLU by the approved (intravenous) route consistently eliminated the drug before the approved withdrawal times; however, residues can persist beyond these approved times following intramuscular or subcutaneous administration. Cows producing less than 20 kg of milk/d had altered FLU milk clearance, which may also contribute to violative FLU residues.