@article{kissell_brinson_gehring_tell_wetzlich_baynes_riviere_smith_2016, title={Pharmacokinetics and tissue elimination of flunixin in veal calves}, volume={77}, ISSN={0002-9645}, url={http://dx.doi.org/10.2460/ajvr.77.6.634}, DOI={10.2460/ajvr.77.6.634}, abstractNote={Abstract
OBJECTIVE To describe plasma pharmacokinetic parameters and tissue elimination of flunixin in veal calves.
ANIMALS 20 unweaned Holstein calves between 3 and 6 weeks old.
PROCEDURES Each calf received flunixin (2.2 mg/kg, IV, q 24 h) for 3 days. Blood samples were collected from all calves before the first dose and at predetermined times after the first and last doses. Beginning 24 hours after injection of the last dose, 4 calves were euthanized each day for 5 days. Plasma and tissue samples were analyzed by ultraperformance liquid chromatography. Pharmacokinetic parameters were calculated by compartmental and noncompartmental methods.
RESULTS Mean ± SD plasma flunixin elimination half-life, residence time, and clearance were 1.32 ± 0.94 hours, 12.54 ± 10.96 hours, and 64.6 ± 40.7 mL/h/kg, respectively. Mean hepatic and muscle flunixin concentrations decreased to below FDA-established tolerance limits (0.125 and 0.025 μg/mL, respectively) for adult cattle by 3 and 2 days, respectively, after injection of the last dose of flunixin. Detectable flunixin concentrations were present in both the liver and muscle for at least 5 days after injection of the last dose.
CONCLUSIONS AND CLINICAL RELEVANCE The labeled slaughter withdrawal interval for flunixin in adult cattle is 4 days. Because administration of flunixin to veal calves represents extralabel drug use, any detectable flunixin concentrations in edible tissues are considered a violation. Results indicated that a slaughter withdrawal interval of several weeks may be necessary to ensure that violative tissue residues of flunixin are not detected in veal calves treated with that drug.}, number={6}, journal={American Journal of Veterinary Research}, publisher={American Veterinary Medical Association (AVMA)}, author={Kissell, Lindsey W. and Brinson, Patrick D. and Gehring, Ronette and Tell, Lisa A. and Wetzlich, Scott E. and Baynes, Ronald E. and Riviere, Jim E. and Smith, Geof W.}, year={2016}, month={Jun}, pages={634–640} }
 @article{kissell_leavens_baynes_riviere_smith_2015, title={Comparison of pharmacokinetics and milk elimination of flunixin in healthy cows and cows with mastitis}, volume={246}, ISSN={["1943-569X"]}, DOI={10.2460/javma.246.1.118}, abstractNote={Abstract
Objective—To determine whether pharmacokinetics and milk elimination of flunixin and 5-hydroxy flunixin differed between healthy and mastitic cows.
Design—Prospective controlled clinical trial.
Animals—20 lactating Holstein cows.
Procedures—Cows with mastitis and matched control cows received flunixin IV, ceftiofur IM, and cephapirin or ceftiofur, intramammary. Blood samples were collected before (time 0) and 0.25, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours after flunixin administration. Composite milk samples were collected at 0, 2, 12, 24, 36, 48, 60, 72, 84, and 96 hours. Plasma and milk samples were analyzed by use of ultra–high-performance liquid chromatography with mass spectrometric detection.
Results—For flunixin in plasma samples, differences in area under the concentration-time curve and clearance were detected between groups. Differences in flunixin and 5-hydroxy flunixin concentrations in milk were detected at various time points. At 36 hours after flunixin administration (milk withdrawal time), 8 cows with mastitis had 5-hydroxy flunixin concentrations higher than the tolerance limit (ie, residues). Flunixin residues persisted in milk up to 60 hours after administration in 3 of 10 mastitic cows.
Conclusions and Clinical Relevance—Pharmacokinetics and elimination of flunixin and 5-hydroxy flunixin in milk differed between mastitic and healthy cows, resulting in violative residues. This may partially explain the high number of flunixin residues reported in beef and dairy cattle. This study also raised questions as to whether healthy animals should be used when determining withdrawal times for meat and milk.}, number={1}, journal={JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION}, author={Kissell, Lindsey W. and Leavens, Teresa L. and Baynes, Ronald E. and Riviere, Jim E. and Smith, Geof W.}, year={2015}, month={Jan}, pages={118–125} }
 @article{leavens_tell_kissell_smith_smith_wagner_shelver_wu_baynes_riviere_et al._2014, title={Development of a physiologically based pharmacokinetic model for flunixin in cattle (Bos taurus)}, volume={31}, ISSN={["1944-0057"]}, DOI={10.1080/19440049.2014.938363}, abstractNote={Frequent violation of flunixin residues in tissues from cattle has been attributed to non-compliance with the USFDA-approved route of administration and withdrawal time. However, the effect of administration route and physiological differences among animals on tissue depletion has not been determined. The objective of this work was to develop a physiologically based pharmacokinetic (PBPK) model to predict plasma, liver and milk concentrations of flunixin in cattle following intravenous (i.v.), intramuscular (i.m.) or subcutaneous (s.c.) administration for use as a tool to determine factors that may affect the withdrawal time. The PBPK model included blood flow-limited distribution in all tissues and elimination in the liver, kidney and milk. Regeneration of parent flunixin due to enterohepatic recirculation and hydrolysis of conjugated metabolites was incorporated in the liver compartment. Values for physiological parameters were obtained from the literature, and partition coefficients for all tissues but liver and kidney were derived empirically. Liver and kidney partition coefficients and elimination parameters were estimated for 14 pharmacokinetic studies (including five crossover studies) from the literature or government sources in which flunixin was administered i.v., i.m. or s.c. Model simulations compared well with data for the matrices following all routes of administration. Influential model parameters included those that may be age or disease-dependent, such as clearance and rate of milk production. Based on the model, route of administration would not affect the estimated days to reach the tolerance concentration (0.125 mg kg−1) in the liver of treated cattle. The majority of USDA-reported violative residues in liver were below the upper uncertainty predictions based on estimated parameters, which suggests the need to consider variability due to disease and age in establishing withdrawal intervals for drugs used in food animals. The model predicted that extravascular routes of administration prolonged flunixin concentrations in milk, which could result in violative milk residues in treated cattle.}, number={9}, journal={FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT}, author={Leavens, Teresa and Tell, L. A. and Kissell, L. W. and Smith, G. W. and Smith, D. J. and Wagner, S. A. and Shelver, W. L. and Wu, H. L. and Baynes, R. E. and Riviere, J. E. and et al.}, year={2014}, month={Sep}, pages={1506–1521} }
 @article{kissell_baynes_riviere_smith_2013, title={Occurrence of flunixin residues in bovine milk samples from the USA}, volume={30}, ISSN={1944-0049 1944-0057}, url={http://dx.doi.org/10.1080/19440049.2013.803604}, DOI={10.1080/19440049.2013.803604}, abstractNote={5-Hydroxy-flunixin concentrations in milk samples were quantified by two commercially available screening assays – CHARM® and enzyme-linked immunoabsorbant assay (ELISA) – to determine whether any concentrations could be detected above the tolerance limit of 2 ng g−1 from different regions in the United States. Milk samples came from large tanker trucks hauling milk to processing plants, and had already been screened for antibiotics. Positive results for flunixin residues based on a screening assay were confirmed by ultra-HPLC with mass spectrometric detection. Of the 500 milk samples analysed in this study, one sample was found to have a 5-hydroxy-flunixin concentration greater than the tolerance limit. The results of this study indicate that flunixin residues in milk are possible. Regulatory agencies should be aware that such residues can occur, and should consider incorporating or expanding flunixin screening tests as part of routine drug monitoring in milk. Larger studies are needed to determine the true prevalence of flunixin residues in milk from other regions in the United States as well as different countries.}, number={9}, journal={Food Additives & Contaminants: Part A}, publisher={Informa UK Limited}, author={Kissell, L.W. and Baynes, R.E. and Riviere, J.E. and Smith, G.W.}, year={2013}, month={Sep}, pages={1513–1516} }
 @misc{baynes_dedonder_kissell_mzyk_marmulak_smith_tell_gehring_davis_riviere, title={Health concerns and management of select veterinary drug residues}, volume={88}, journal={Food and Chemical Toxicology}, author={Baynes, R. E. and Dedonder, K. and Kissell, L. and Mzyk, D. and Marmulak, T. and Smith, G. and Tell, L. and Gehring, R. and Davis, J. and Riviere, J. E.}, pages={112–122} }