Factors Influencing the Pharmacokinetics and Milk Elimination of Flunixin in Dairy Cattle

Drug residues in the food supply are both an economical and human health safety concern. Flunixin (FLU) is a non-steroidal anti-inflammatory drug labeled for use in beef and dairy cattle for the modulation of inflammation in endotoxemia and for the control of pyrexia associated with bovine respiratory disease, endotoxemia and acute bovine mastitis. The United States Department of Agriculture-Food Safety Inspection Service has reported an increasing number of residue violations in meat from dairy cattle resulting in FLU becoming the second most common residue violation behind penicillin in cull dairy cattle (USDAFSIS, 2005-2010). Currently, milk is not routinely tested for FLU residues; however, because a significant number of FLU tissue residue violations are found in cull dairy cows, a concern exists that the same practices which have lead to tissue residue violations may also be leading to FLU milk residue violations. Therefore, a surveillance study of saleable milk collected from processing plants in the United States was conducted to determine whether violative FLU residues could be found in milk. Five hundred milk samples were analyzed for 5- hydroxy flunixin (5OH), the milk marker residue. Of the five hundred milk samples, 1 sample was positive for 5OH above the tolerance limit. The results of this study indicate that violative FLU residues in milk are possible; however, what may cause a violative milk residue is unknown. Therefore two experiments were conducted to investigate potential situations that could result in violative FLU milk residues.;The first experiment used a crossover design to determine the pharmacokinetics and milk elimination of FLU and 5OH in lactating dairy cows following intravenous, intramuscular and subcutaneous administration. The results showed differences in several plasma pharmacokinetic parameters following extravascular administration compared to intravenous administration. Using non linear mixed effects modeling, the decrease in 5OH milk concentration versus time was analyzed. The model indicated that both route of administration and rate of milk production were significant covariates. When FLU was administered either intramuscularly or subcutaneously, some cattle had 5OH residues greater than the tolerance limit in the milk at the labeled withdrawal time. Cattle that received FLU by the approved route (intravenous) eliminated the drug before the approved withdrawal time. This study shows that FLU residues identified in milk may be related to administration of FLU by an unapproved route.;The second experiment was a prospective clinical trial where 10 cows with naturally occurring mastitis and 10 healthy paired controls were administered FLU to determine if FLU and 5OH plasma pharmacokinetics and milk elimination differed between healthy and mastitic cows. Analysis of plasma samples indicated a significant reduction in plasma clearance, an increase in the area under the concentration time curve from time zero to infinity, and prolonged mean residence time in diseased versus healthy cows. Analysis of milk samples showed significant differences in FLU and 5OH milk concentrations at various time points. At the 36-hour milk withdrawal time, 8 cows with mastitis had 5OH residues greater than the tolerance limit. FLU residues persisted in the milk up to 60 hours post administration for 3 out of 10 of the mastitic cows. This study provides strong evidence that milk withdrawal times determined in healthy cattle may not be appropriate in cows with clinical mastitis. Our results also suggest that the use of a marker residue, such as 5OH is of concern since its ratio to parent compound (FLU) changes in the very disease for which it is labeled.;Violative FLU residues in milk from dairy cattle are likely due to multiple factors; primarily extralabel drug use and alterations in clearance as result of a disease process. Therefore, education of veterinarians and farm personnel in proper drug administration and determining a milk withdrawal time under the condition in which a drug is labeled for is critical in the prevention of residue violations.