Objective:To assess the pharmacokinetics of a single application of transdermal flunixin meglumine in southern white rhinoceros (Ceratotherium simum simum). Methods:Healthy adult white rhinoceros were prospectively enrolled in the study from June through September 2024. Baseline blood samples were collected prior to drug administration. A single (3.3 mg/kg) dose of commercially available transdermal flunixin meglumine was applied topically at 2 primary sites: the nuchal hump extending behind the ears and the skin overlying the spine from the shoulder to ischium. Blood samples were collected under behavioral restraint at 2 to 4 time points for each rhinoceros following a sparse-sampling model. Drug assay validation and plasma drug concentrations were determined using HPLC-MS-MS. Results:Successful application of transdermal flunixin meglumine was achieved in 13 individuals. Twelve individuals were included in compartmental analysis. The time to maximum plasma concentration was 7.2 hours. The peak plasma concentration was 0.31 μg/mL. The elimination half-life was 28.6 hours. Mild behavioral changes were observed in 6 animals and included quiet mentation, rubbing at the application site, lethargy, and mild ataxia. All side effects were noted to be resolved 24 hours after drug application. Conclusions:Transdermal flunixin meglumine was absorbed and measurable plasma concentrations achieved in all southern white rhinoceros. The side effects observed included short-duration behavioral changes. Clinical Relevance:This study reports successful use and pharmacokinetic parameters of transdermal flunixin meglumine at 3.3 mg/kg when applied to the neck and topline in southern white rhinoceros.

BackgroundFlunixin is commonly used in goats in an extra-label manner, indicating a significant need to determine withdrawal intervals for edible tissues.ObjectiveThe objectives of the present study were to investigate the depletion of flunixin meglumine in various goat tissues, including the liver, kidney, fat, and muscle.MethodsTwenty Boer goats were enrolled and administered an intravenous dose (2.2 mg/kg) of flunixin meglumine. Five animals were randomly euthanized at 24, 48, 72, or 96 h following dosing. All samples were analyzed via ultra-performance liquid chromatography coupled with mass spectrometry.ResultsThe concentration of flunixin in all tissues declined rapidly, with the highest mean concentrations quantified in the kidney (0.137 ± 0.062 μg/g) and liver (0.077 ± 0.029 μg/g) tissues at 24 h.ConclusionSince any detection of flunixin residues at slaughter found in goat tissues is considered a violative residue, a conservative withdrawal interval of 17 days was calculated to ensure levels of flunixin fell below the regulatory limits of detection in liver, kidney, and muscle tissues.

AbstractBackgroundPharmacological activity of intramammary drugs depends on adequate drug concentrations within the cistern, but sampling is often limited. Insight into the active drug concentration within the mammary cistern may assist in determining effective and appropriate therapeutic decisions for cows being treated for mastitis.ObjectiveEvaluate the disposition of ceftiofur hydrochloride administered intramammary in diseased and nondiseased quarters. Whole milk and ultrafiltrate sampling techniques were compared.AnimalsTen mature, late lactation Holstein (n = 9) and Jersey (n = 1) dairy cows (422‐670 kg) with naturally occurring clinical mastitis, producing between 1.4 and 15.9 kg/day of milk.MethodsUltrafiltration probes were placed in both mastitic and healthy quarters. Each quarter was treated with 2 doses of 125 mg ceftiofur hydrochloride suspension, and whole milk and milk ultrafiltrate samples were collected. Ceftiofur concentrations in composite whole milk and milk ultrafiltrate were analyzed.ResultsThe maximum concentration of ceftiofur was higher in ultrafiltrate samples, but no differences were identified in healthy or mastitic quarters. The use of ultrafiltration probes provides a novel technique for free drug concentrations within the mastitic and healthy bovine mammary gland.Conclusions and Clinical ImportanceSignificant inter‐ and intracow variability and lower daily milk weights may overestimate ceftiofur concentrations available within the cistern. The pharmacokinetic (PK) parameters reported in milk ultrafiltrate will help establish a link between the PK and the corresponding drug effect, potentially providing a meaningful rationale for the selection of a safe and effective dose in cows with mastitis.

OBJECTIVE:To determine the influence of stage of lactation on the pharmacokinetics in milk when multiple doses of meloxicam were administered alone or in combination with gabapentin to postpartum (PP) and mid-lactation (ML) cows.ANIMALS:8 postpartum and 8 mid-lactation dairy cows.METHODS:Cows were randomly divided into 2 groups (n = 8) which included 4 PP cows and 4 ML cows. Group I received only 6 oral daily doses of meloxicam (1.0 mg/kg for 6 doses). Group II received 6 oral daily doses of co-administered meloxicam (1.0 mg/kg) and gabapentin (20 mg/kg) for 6 doses. Meloxicam and gabapentin were quantified in plasma and milk samples by ultra-high-performance liquid chromatography-tandem mass spectrometry, and the pharmacokinetic analysis of milk and plasma was performed using a non-compartmental approach.RESULTS:Regardless of lactation status, dairy cattle administered multiple doses of meloxicam and/or gabapentin showed low drug residue concentrations and little accumulation in milk. The terminal plasma half-life of meloxicam was significantly increased (P < .02) in PP cows (12.9 hr) compared to ML cows (9.4 hr). The apparent terminal half-life in milk for meloxicam and gabapentin was not affected by stage of lactation. Co-administration of gabapentin did not alter plasma or milk concentrations of meloxicam.CLINICAL RELEVANCE:The results of this study suggest that milk from cows treated with multiple doses of meloxicam alone or in combination with gabapentin will have low drug concentrations and falls below our reported limit of detection for meloxicam or gabapentin 120 and 60 hours respectively, following the final dose regardless of their stage of lactation.

•Grapiprant was evaluated in goat kids as a potential anti-inflammatory medication.•There were no adverse effects noted with two different administrations.•Plasma concentrations reached peaks correlated with reducing pain in other models.

Management of pain is a significant welfare concern for lactating dairy cattle. There is a lack of approved pain medications for lactating dairy cattle. A combination therapy of gabapentin, a GABA analog and meloxicam, a nonsteroidal anti-inflammatory drug, are commonly used for analgesia in cattle in an extra-label manner. The objective of this study was to determine the number of days milk residues could be detected when meloxicam was administered alone or in combination with gabapentin in both postpartum and midlactation cows following multiple doses.

Pneumonia is one of the most economically important respiratory diseases of calves and knowledge of the impact of clinical disease on pharmacokinetics (PK) in young calves is limited. This study was undertaken to investigate the efficacy and PK of two antibiotics, tulathromycin and danofloxacin, in two age groups of calves experimentally infected with Pasteurella multocida. Both danofloxacin, a fluoroquinolone antibiotic, and tulathromycin, a macrolide antibiotic is approved for the treatment of bovine respiratory disease (BRD). To evaluate potential influences of age and disease on drug distribution and elimination in calves, plasma, interstitial fluid (ISF), and pulmonary epithelial lining fluid (PELF) were analyzed for drug concentrations. Concentrations for both drugs in the PELF were estimated by a urea dilution assay of the collected bronchoalveolar lavage fluids. Age was determined to be a significant covariate for calves administered danofloxacin and tulathromycin for plasma PK parameters. For calves administered danofloxacin, the area under the curve (AUC) in the plasma was lower in 6-month old calves (18.9 ± 12.6 hr* μg/mL) vs. 3-week old calves (32.0 ± 8.2 hr* μg/mL). Clearance (CL/F) of danofloxacin was higher in 6-month old calves. In contrast, tulathromycin plasma concentrations were higher in 6 month old calves and CL/F was higher in 3-week old calves. Age did not significantly influence the ISF concentrations of danofloxacin or tulathromycin in calves with respiratory disease, unlike previous studies which reported higher ISF concentrations of danofloxacin and tulathromycin in 6-month old calves when compared to younger calves. PELF concentrations were higher than plasma and ISF for both danofloxacin and tulathromycin, but did not differ between age groups. Potential reasons for age-related differences on plasma concentration-time profiles and the impact of disease on the partitioning of the drug from the blood to the lungs and ISF as a function of age are explored.

The allowable tolerance for a drug is based on edible tissue, yet a majority of livestock shows use urine samples to test for the presence of performance enhancing drugs. Currently, there is limited data on the relationship between urine and plasma or target tissue concentrations used for withdrawal time calculations in food animal species. Therefore, the objective of this study was to compare plasma and urine concentrations in goats administered 1 of 2 nonsteroidal anti-inflammatory drugs, flunixin meglumine and meloxicam, in order to determine withdrawal intervals for animals where urine is routinely tested at livestock shows.

The intent of this study was to determine what influence, if any, increasing age has on the binding of drugs to plasma proteins in cattle. Plasma from three different cohorts of calves were used. The first group (n = 20) had plasma samples taken at 1, 7 and 21 days of age. These were compared to results from a second group of calves at 8 weeks and third group sampled at 6 months of age. The plasma protein binding of danofloxacin, florfenicol, flunixin meglumine and tulathromycin was determined in vitro via microcentrifugation using three different drug concentrations spiked into the individual plasma samples derived from each calf. Albumin concentrations were lowest at 1 day of age as compared to plasma samples taken from 2 month old and 6 month old calves. There were significant decreases in alpha1-acid glycoprotein in calves until 21 days of age. However, statistically significant age-effects on plasma protein binding were not observed for any of the drugs evaluated in this study. Findings from these calves suggest that age is not an important factor in the binding of these drugs to plasma proteins.

Pharmacokinetic studies of the drugs in the milk are often limited due to infrequent sampling associated with milking. Alternatively, frequent sample collection with repeated milking may increase drug elimination. The objective of this study was to determine the feasibility of continuously sampling the udder using ultrafiltration. An ultrafiltration probe was placed into the gland cisterns through mammary parenchyma of normal and mastitic quarters of 6 mature mid-lactation Jersey cows with naturally occurring subclinical mastitis. An ultrafiltration probe was secured to the caudal or lateral aspect of the udder depending on the quarter being sampled. The timed interval samples were collected at 0, 2, 4, 6, 8, 12, 18, 24, 28, 32, 36, 48, 60, 72, 84, and 96 h after drug administration. Plasma samples were collected at the same time points. Each cow received 2.2 mg/kg of flunixin intravenously before milking at time 0. All cows were routinely milked by machine every 12 h. Flunixin concentrations in plasma, whole milk, and milk ultrafiltrates were analyzed by use of ultra-high-performance liquid chromatography with mass spectrometric detection. We found no significant effects on the appearance of the milk or the ability to milk the cows after implantation of the ultrafiltration probes. The concentration of flunixin collected from the ultrafiltration probes in the mastitic quarters tended to be greater than that of the healthy quarters. We concluded that collection of ultrafiltration samples from the mammary gland of cows provides a viable means to continuously assess drug concentrations in the milk while continuing to milk the cow normally. This study demonstrates the utility of continuous sampling of milk via ultrafiltration for future pharmacokinetic studies in cattle.

The allowable tolerance for a drug is based on edible tissue, yet a majority of livestock shows use urine samples to test for the presence of performance enhancing drugs. Currently, there is limited data on the relationship between urine and plasma or target tissue concentrations used for withdrawal time calculations in food animal species. Therefore, the objective of this study was to compare plasma and urine concentrations in goats administered 1 of 2 nonsteroidal anti-inflammatory drugs, flunixin meglumine and meloxicam, in order to determine withdrawal intervals for animals where urine is routinely tested at livestock shows.

OBJECTIVE To compare the plasma pharmacokinetics of tulathromycin between 3-week-old (preweaned) and 6-month-old (weaned) calves and to characterize the distribution of tulathromcyin into pulmonary epithelial lining fluid (PELF) and interstitial fluid (ISF) of preweaned and weaned calves following SC administration of a single dose (2.5 mg/kg). ANIMALS 8 healthy 3-week-old and 8 healthy 6-month-old Holstein steers. PROCEDURES A jugular catheter and SC ultrafiltration probe were aseptically placed in the neck of each calf before tulathromycin administration. Blood, ISF, and bronchoalveolar lavage fluid samples were collected at predetermined times before and after tulathromycin administration for quantification of drug concentration. A urea dilution method was used to estimate tulathromycin concentration in PELF from that in bronchoalveolar lavage fluid. Tulathromycin-plasma protein binding was determined by in vitro methods. Plasma pharmacokinetics were determined by a 2-compartment model. Pharmacokinetic parameters and drug concentrations were compared between preweaned and weaned calves. RESULTS Clearance and volume of distribution per fraction of tulathromycin absorbed were significantly greater for weaned calves than preweaned calves. Tulathromycin-plasma protein binding was significantly greater for weaned calves than preweaned calves. Maximum PELF tulathromycin concentration was significantly greater than the maximum plasma and maximum ISF tulathromycin concentrations in both groups. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that age affected multiple pharmacokinetic parameters of tulathromycin, likely owing to physiologic changes as calves mature from preruminants to ruminants. Knowledge of those changes may be useful in the development of studies to evaluate potential dose adjustments during treatment of calves with respiratory tract disease.

A program was written in R to facilitate the implementation of the tolerance limit method (TLM) for establishing regulatory withdrawal times for limiting drug residues in meat, milk, and eggs. The developed computer source code can use pharmacokinetic and regulatory data to calculate the drug withdrawal period according to United States Food and Drug Administration (U.S. FDA) guidelines. The code called the “Withdrawal Time Calculator (WTC)” applied this TLM method to meat samples. The program was tested with the data provided by the U.S. FDA guidance and other published data collected from in vivo studies. Additional algorithm validation data were flunixin and sulfamethazine liver concentration data from peer-reviewed publications generated by our laboratory. This manuscript reports the withdrawal period results from testing the developed WTC code. Moreover, the source code for the WTC contains a data removal algorithm, constructed according to U.S. FDA data elimination recommendations if the user chooses. The power of the WTC is that it bypasses the use of multiple platforms typically required to perform the TLM, including standard commercial spreadsheet software (i.e., Microsoft Excel) and Statistical Analysis System (SAS) while providing speed and usability. This novel program provides a platform to calculate a withdrawal period recommendation for any drug in any class of animal for various regulatory body standards and could be very helpful in cases of extra-label drug use in food animals.

Safety of food originated from animals is an emerging global health problem, and ensuring food safety is a challenge for the producers and governments who deal with protecting the food supply chain from contamination with hazardous microbes, chemicals and/or drugs. In the United States (US), the Food Animal Residue Avoidance Databank (FARAD) program is a unique consortium of scientific experts who help maintain a proper balance among animal health, food safety, and regulatory policies. Veterinarians must often use drugs in an extra-label manner to treat food animals due to limited availability of Food and Drug Administration (FDA) approved drugs. Extra-label drug use (ELDU) is allowable under the Animal Medicinal Drug Use Clarification Act (AMDUCA). Following ELDU, and before products derived from the treated animal can be sold and marketed, an extended withdrawal time (EWDT) needs to be established, based on appropriate scientific data. The objective of this paper is to discuss the scientific basis for determination of EWDT of drugs used in food animals using kinetic modeling approach.

1275 Calfhood diseases have major negative economic consequences on beef and dairy operations owing to costs associated with treatment, long-term effects on growth and performance, and death of affected calves.1–3 The number of drugs approved for the treatment of diseased calves by the FDA is limited; however, veterinarians have the authority to administer drugs in an extralabel manner to that class of animals under provisions established by AMDUCA.4 Nevertheless, drug labels that state, “a withdrawal period has not been established for this product in preruminating calves” can cause confusion about whether those drugs can or cannot be administered to young calves. Pharmacokinetic and residue depletion studies for very few drugs have been performed in young calves, and extrapolation of drug WDTs established for adult cattle to calves might not be appropriate or adequate to avoid violative tissue residues, which makes ELDU in calves problematic and potentially difficult to justify. The purpose of this digest is to provide veterinarians with a summary of the considerations for ELDU in both beef and dairy calves as well as calves intended for veal production.

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.

The objective of this study was to compare active drug concentrations in the plasma vs. different effector compartments including interstitial fluid (ISF) and pulmonary epithelial lining fluid (PELF) of healthy preruminating (3-week-old) and ruminating (6-month-old) calves. Eight calves in each age group were given a single subcutaneous (s.c.) dose (8 mg/kg) of danofloxacin. Plasma, ISF, and bronchoalveolar lavage (BAL) fluid were collected over 96 h and analyzed by high-pressure liquid chromatography. PELF concentrations were calculated by a urea dilution assay of the BAL fluids. Plasma protein binding was measured using a microcentrifugation system. For most preruminant and ruminant calves, the concentration-time profile of the central compartment was best described by a two-compartment open body model. For some calves, a third compartment was also observed. The time to maximum concentration in the plasma was longer in preruminating calves (3.1 h) vs. ruminating calves (1.4 h). Clearance (CL/F) was 385.15 and 535.11 mL/h/kg in preruminant and ruminant calves, respectively. Ruminant calves maintained higher ISF/plasma concentration ratios throughout the study period compared to that observed in preruminant calves. Potential reasons for age-related differences in plasma concentration-time profiles and partitioning of the drug to lungs and ISF as a function of age are explored.