The Impact of Infection and Inflammation on Drug Metabolism, Active Transport, and Systemic Drug Concentrations in Veterinary Species.

Within human medicine, it is recognized that the pharmacokinetics (PK) of many compounds can be altered by the presence of inflammation or infection. Research into the reason for these changes has identified pathways that can influence drug absorption, clearance, and tissue distribution. In contrast, far less is known about these relationships within the framework of veterinary medicine. Rather, most of the PK data generated in veterinary species employs healthy subjects, raising the question of whether these studies are founded on an assumption that healthy animal PK reflect that of the diseased animal population. Accordingly, there is a need to explore the PK changes that might be overlooked in studies that recruit only healthy animals to assesses drug PK. To meet this objective, we surveyed the published literature for studies focusing on the impact of disease on the dose-exposure relationships in food-producing and companion animal species. We found that, consistent with humans and laboratory species, both up- and downregulation of the various cytochrome isoenzymes and/or transporters have occurred in response to an increase in inflammatory mediators. These findings suggest that, as observed in human medicine, the potential for differences in the drug PK in healthy versus animal patients points to a need for acquiring a greater understanding of these changes and how they may influence the dose-exposure-response relationships of veterinary pharmaceuticals. SIGNIFICANCE STATEMENT: This review delivers a much-needed summary of published information that provides insights into how disease and inflammation can influence the appropriateness of extrapolating laboratory-based dose-exposure-response relationships to what will occur in the actual veterinary patient. As part of this review, we also examine some of the method-associated issues to be considered when assessing the reported nature and magnitude of these changes.

Pharmacokinetics and tissue elimination of flunixin in veal calves.

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.

Health concerns and management of select veterinary drug residues.

The aim of this manuscript is to review the potential adverse health effects in humans if exposed to residues of selected veterinary drugs used in food-producing animals. Our other objectives are to briefly inform the reader of why many of these drugs are or were approved for use in livestock production and how drug residues can be mitigated for these drugs. The selected drugs include several antimicrobials, beta agonists, and phenylbutazone. The antimicrobials continue to be of regulatory concern not only because of their acute adverse effects but also because their use as growth promoters have been linked to antimicrobial resistance. Furthermore, nitroimidazoles and arsenicals are no longer approved for use in food animals in most jurisdictions. In recent years, the risk assessment and risk management of beta agonists, have been the focus of national and international agencies and this manuscript attempts to review the pharmacology of these drugs and regulatory challenges. Several of the drugs selected for this review can cause noncancer effects (e.g., penicillins) and others are potential carcinogens (e.g., nitroimidazoles). This review also focuses on how regulatory and independent organizations manage the risk of these veterinary drugs based on data from human health risk assessments.

Comparison of pharmacokinetics and milk elimination of flunixin in healthy cows and cows with mastitis.

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.

Development of a physiologically based pharmacokinetic model for flunixin in cattle (Bos taurus).

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.