Arthur L. Craigmill

Pharmacokinetics of butorphanol tartrate in red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus)

OBJECTIVE To determine the pharmacokinetics of butorphanol tartrate after IV and IM single-dose administration in red-tailed hawks (RTHs) and great horned owls (GHOs). ANIMALS 6 adult RTHs and 6 adult GHOs. PROCEDURES Each bird received an injection of butorphanol (0.5 mg/kg) into either the right jugular vein (IVj) or the pectoral muscles in a crossover study (1-week interval between treatments). The GHOs also later received butorphanol (0.5 mg/kg) via injection into a medial metatarsal vein (IVm). During each 24-hour postinjection period, blood samples were collected from each bird; plasma butorphanol concentrations were determined via liquid chromatography-mass spectrometry. RESULTS 2- and 1-compartment models best fit the IV and IM pharmacokinetic data, respectively, in both species. Terminal half-lives of butorphanol were 0.94 +/- 0.30 hours (IVj) and 0.94 +/- 0.26 hours (IM) for RTHs and 1.79 +/- 1.36 hours (IVj), 1.84 +/- 1.56 hours (IM), and 1.19 +/- 0.34 hours (IVm) for GHOs. In GHOs, area under the curve (0 to infinity) for butorphanol after IVj or IM administration exceeded values in RTHs; GHO values after IM and IVm administration were less than those after IVj administration. Plasma butorphanol clearance was significantly more rapid in the RTHs. Bioavailability of butorphanol administered IM was 97.6 +/- 33.2% (RTHs) and 88.8 +/- 4.8% (GHOs). CONCLUSIONS AND CLINICAL RELEVANCE In RTHs and GHOs, butorphanol was rapidly absorbed and distributed via all routes of administration; the drugs rapid terminal half-life indicated that published dosing intervals for birds may be inadequate in RTHs and GHOs.

Pharmacokinetics of ceftiofur and metabolites after single intravenous and intramuscular administration and multiple intramuscular administrations of ceftiofur sodium to sheep

Twenty-four sheep (38.0-54.1 kg body wt) were allocated into four treatment groups and dosed with ceftiofur sodium at 1.1 mg ceftiofur free acid equivalents (CFAE)/kg or 2.2 CFAE/kg using a complete two-route (intravenous, i.v.: intramuscular, i.m.), two-period crossover design, with a two-week washout between injections. After another two-week washout period, 12 sheep were selected and dosed with ceftiofur sodium i.m. for five consecutive days at either 1.1 or 2.2 mg CFAE/kg. After all injections, blood samples were obtained serially for determination of serum concentrations of ceftiofur and metabolites. The terminal phase half-lives derived from the last 3-5 concentration-time points were 350 and 292 min (harmonic means) after i.v. doses of 1.1 and 2.2 mg/kg, respectively, and 389 and 459 min after i.m. doses of 1.1 and 2.2 mg/kg, respectively. The i.m. bioavailability of ceftiofur sodium in sheep was 100%, and the area under the curve from time 0 to the limit of quantitation (AUC0 LOQ) was dose-proportional from 1.1-2.2 mg CFAE/kg body wt in sheep. After 5 daily i.m. doses of ceftiofur sodium at either 1.1 or 2.2 mg CFAE/kg there was minimal accumulation of drug in serum as assessed by the observed maximum serum concentration (Cmax), and serum concentrations were dose-proportional after the multiple dosing regimen.

Handbook of comparative pharmacokinetics and residues of veterinary antimicrobials.

The major objective of this handbook is to compile-in tabular form-the pharmacokinetic parameters of antimicrobial drugs used in food animals. This unique publication represents data from the FARAD (Food Animal Residue Avoidance Databank) databank, established by the authors under the auspices of the U.S.D.A. and contains significant amounts of previously unavailable information. This updated, one-of-a-kind volume even features additional data on laboratory rodents, dogs, cats, and horses in order to facilitate broader interspecies extrapolations. This easy-to-use reference is timely as well as invaluable to animal scientists, veterinarians, pharmacologists, and toxicologists who work with antimicrobials in chickens, turkeys, dairy and beef cattle, swine, goats, and sheep.

A PBPK model for midazolam in four avian species.

A physiologically based pharmacokinetic (PBPK) model was developed for midazolam in the chicken and extended to three other species. Physiological parameters included organ weights obtained from 10 birds of each species and blood flows obtained from the literature. Partition coefficients for midazolam in tissues vs. plasma were estimated from drug residue data obtained at slaughter. The avian models include separate compartments for venous plasma, liver, kidney, muscle, fat and all other tissues. An estimate of total body clearance from an earlier in vitro study was used as a starting value in the model, assuming almost complete removal of the parent compound by liver metabolism. The model was optimized for the chicken with plasma and tissue data from a pharmacokinetic study after intravenous midazolam (5 mg/kg) dose. To determine which parameters had the most influence on the goodness of fit, a sensitivity analysis was performed. The optimized chicken model was then modified for the turkey, pheasant and quail. The models were validated with midazolam plasma and tissue residue data in the turkey, pheasant and quail. The PBPK models in the turkey, pheasant and quail provided good predictions of the observed tissue residues in each species, in particular for liver and kidney.

Feasibility of using half-life multipliers to estimate extended withdrawal intervals following the extralabel use of drugs in food-producing animals.

Under the Animal Medicinal Drug Use Clarification Act of 1994, veterinarians are legally allowed to use drugs in food-producing animals in an extralabel manner. This could potentially lead to violative residues in food of animal origin. It is therefore essential that an appropriately extended withdrawal interval be established. Ideally, these extended withdrawal intervals should be calculated on the basis of the tissue half-life of the drug in the target animal. However, these data are not readily available for all drugs of extralabel use in food-producing animals. For this reason, the use of a half-life multiplier has been proposed as a simple alternative method to estimate the effective tissue half-life of a drug. Extended withdrawal intervals, estimated using various half-life multipliers, were compared with the withdrawal intervals calculated using actual tissue half-lives. For the group of drugs investigated, a half-life multiplier of 5 resulted in estimates of extended withdrawal intervals that were potentially inadequate to prevent violative tissue residues for drugs that had relatively long tissue half-lives, high tolerances, or both. This is possibly because fewer half-lives are required for these drugs to reach the target tissue concentrations following administration at label doses. Use of a smaller half-life multiplier (in this case 3) is therefore suggested to ensure that extended withdrawal intervals are adequate to prevent violative tissue residues.

Tissue residues of florfenicol in sheep

Nuflor (florfenicol) Injectable Solution is approved for use in beef cattle (NADA 141-063) for the treatment of bovine respiratory disease associated with Mannheimia (Pasteurella) haemolytica, Pasteurella multocida, and Haemophilus somnus. Respiratory disease in sheep is often caused by the same pathogens as those causing disease in cattle. The pharmacokinetics of florfenicol in sheep after intravenous and subcutaneous (Lane et al., 2004), and intramuscular (Shen et al., 2004) dosing have been described previously and the MICs of florfenicol for sheep respiratory pathogens are similar to those of cattle respiratory pathogens (Berge et al., 2006). As the efficacy of florfenicol for use in the treatment of sheep respiratory pathogens is well established, the primary objective of this study was to provide tissue residue data necessary to fulfill the human food safety requirements for florfenicol in sheep. This was done by measuring tissue concentrations of florfenicol amine (the marker residue for florfenicol in cattle) after three subcutaneous daily doses of 40 mg ⁄ kg. The secondary objective of the study was to provide target animal safety data on injection site irritation after subcutaneous injections. This was done by gross pathology of each injection site at the time of necropsy. All of the protocols for this study were approved by the UC Davis IACUC. Twenty-six healthy mixed breed 6to 7-month-old sheep (13 male wethers, 13 female), weighing from 40.3 to 65 kg (51.4 ± 5.9) were the subjects. Each sheep was uniquely identified with ear tags and ear notches. The sheep were randomly allocated to groups using the following procedure: the sheep were listed from lightest to heaviest by sex based on the weight taken during the prestudy physical examination. The five lightest and five heaviest of each sex were then randomly assigned to five treatment groups. The six remaining animals were then randomly assigned to the treatment groups with the sixth animal acting as the control. The treatment groups were then randomly assigned to the slaughter time points (5, 10, 20, 30 and 40 days). The sheep were fed 2.5 kg of pellets (70% alfalfa ⁄ 30% corn) per head daily. Sheep were housed outside with access to shelter from rain and sun. Automatic watering and salt blocks were provided for ad libitum access. The test animals were brought into indoor test pens for the drug treatments and sample collection. Florfenicol (40 mg ⁄ kg body weight) was injected subcutaneously in the neck area once daily for 3 days using different injection sites for each daily dose. The first and third injections were on the left side and the second injection was on the right side. The first injection was anterior to the third and separated by at least 7.5 cm. Dose volumes were determined based on the average body weights obtained the 2 days prior to treatment. If the weights differed by more than 5%, those animals were reweighed a third time just prior to dosing, and the two closest weights averaged to determine the dose. Blood samples were then collected prior to each dose (0, 24 and 48 h), at 24 h intervals for 3 days following the last dose (72, 96 and 120 h) and prior to slaughter for analysis of florfenicol in serum. Groups of five sheep were slaughtered by captive-bolt stunning and exsanguination at 5, 10, 20, 30 and 40 days after the last dose. The following tissues were collected from each animal: a 300 g (approximate) core at a radius of 7.5 cm from injection sites 2 and 3 for residue analysis; both kidneys; the entire liver; 250–500 g of muscle from the left semimembranosus ⁄ semitendinosus muscles; the entire diaphragm; 100–250 g renal fat; and 100–250 g carcass fat. Tissues were stored on ice immediately after collection, then transferred to a )20 C freezer within 4 h of harvest. Tissues were thawed for processing to produce a homogenous ground sample and stored at )80 C until analysis. Processing was carried out over a period of 6 days. Spiked control tissues were handled in exactly the same manner to measure residue stability. Residues were stabile in all tissues throughout the entire analysis period of 85 weeks. J. vet. Pharmacol. Therap. 31, 178–180, doi: 10.1111/j.1365-2885.2007.00918.x. SHORT COMMUNICATION

The Food Animal Residue Avoidance Databank (Farad): Past, Present and Future

During the last one-and-one-half decades, FARAD has established an unparalleled compilation of residue and pharmacokinetic information for veterinary species. In order to fulfill its mission, FARAD has become as much a research project as an educational one. Pressing problems, such as disease-altered kinetics, minor-species drug use, and industrial contaminants in livestock, require the new methods of analysis FARAD is developing. The data upon which this work is based can be greatly augmented by participation by other nations. In the United States, it was the cooperation of both academic and regulatory organizations that made the success of FARAD possible. Similar international cooperation can facilitate use of the FARAD model in other countries for the economic benefit of all participants, enhancement of food safety, and promotion of animal welfare.

Safety, efficacy, and tissues residues of ivermectin in reindeer

Safety, efficacy, and tissue residues of ivermectin, a broad spectrum parasiticide, were determined in Alaskan reindeer ( Rangifer tarandus ). Reindeer treated at 5 times and 10 times the standard dose of 200 mcg/kg had no detectable physical or behavioral reactions to ivermectin injected subcutaneously in the mid-cervical area. Ivermectin eliminated essentially 100% of reindeer warble larvae ( Hypoderma ( Oedemagena ) tarandi ). Tissue levels of ivermectin in back fat, injection site, muscle, liver, and kidney collected 3, 10, 17, and 24 days post injection were determined. All tissues levels rapidly declined and were approaching low unmea-surable amounts at the end of the 24 day test period. Ivermectin is a safe effective parasiticide that has been used successfully to threat thousands of reindeer in Alaska.

PHARMACOKINETICS OF PIPERACILLIN AFTER INTRAMUSCULAR INJECTION IN RED-TAILED HAWKS {BUTEO JAMAICENSIS) AND GREAT HORNED OWLS {BUBO VIRGINIANUS)

Abstract This study characterized and compared the pharmacokinetics of piperacillin after single 100 mg/kg i.m. injections in nine red-tailed hawks (Buteo jamaicensis) and five great horned owls (Bubo virginianus) over 48 hr by a modified agar well diffusion microbial inhibition assay. The mean maximum plasma piperacillin concentrations were 204 µg/ml and 221 µg/ml for the hawks and owls, respectively, and times of maximum concentrations were 15 min and 30 min, respectively. The calculated mean terminal elimination half-lives were 77 min in the hawks and 118 min in the owls. Area-under-the-curve values were 218 ± 52 µg·hr/ml in the hawks and 444 ± 104 µg·hr/ml in the owls. On the basis of the most common minimal inhibitory concentration (90%) for various bacterial isolates from clinical samples of 8 µg/ml, analysis of the data suggests that the maximum dosing interval for piperacillin at 100 mg/kg in medium sized raptors should be 4–6 hr.

Food Animal Residue Avoidance Databank (FARAD): An Automated Pharmacologic Databank for Drug and Chemical Residue Avoidance

The Food Animal Residue Avoidance Databank (FARAD) is a comprehensive computerized databank of regulatory and pharmacologic information useful for mitigation of drug and chemical residue problems in food-producing animals. For drugs, the databank contains information on proprietory products, labelled indications for use, and approved withdrawal and milk discard times. For drugs and chemicals, data are available on physiochemical properties of the chemical or generic drug, on tissue, egg and milk tolerances of these compounds, and on their pharmacokinetic behavior. This latter category is the most unique aspect of FARAD as it involves an extensive statistical analysis of published data, which results in estimates of the rates of depletion of these compounds in target animal species. These data have not been previously available. All data in FARAD are linked to specific sources which are listed in a citation file. Finally, resources produced as a result of USDA Residue Avoidance Program projects are listed in the database. Access to the databank is available at three regional access centers in California (916-752-7507), Illinois (217-333-3611) and Florida (904-392-4085), while the databank is maintained at a data analysis and support center in North Carolina. FARAD presently contains over 7,000 records with information on 250 compounds, and is supported by the USDA-Extension Services Residue Avoidance Program.