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Every chapter has been formatted in an effort to maximize use of the data tabulated. A brief narrative introducing the class of compounds is first presented in order to present an overview of the compounds presented. For frequently used therapeutic drugs, these introductions may be more exten sive. A list of selected readings is provided for more in-depth discussions of these compounds. Chemical structures are then presented for all compounds for which pharmacokinetic data is available. It must be stressed that the tabulation of the pharmacokinetic data in Table 4 of each section is the central reason for compiling this handbook. In order to maximize the use of these data, pertinent ancillary information is also tabulated when available. Every effort has been made to make these ancillary tables as complete as possible: however, data for all parameters for all drugs are not available.

Mehl, M. L., Tell, L., Kyles, A. E., Chen, Y.-J., Craigmill, A., Gregory, C. R. Pharmacokinetics and pharmacodynamics of A77 1726 and leflunomide in domestic cats. J. vet. Pharmacol. Therap. 35, 139–146. The pharmacokinetics and pharmacodynamics of A77 1726 and leflunomide after intravenous (i.v.) and oral (p.o.) administration were evaluated in adult cats. Three treatments were administered: a single i.v. dose of A77 1726 (4 mg/kg), a single oral dose of leflunomide (4 mg/kg), and multiple oral doses of leflunomide (2 mg/kg). Mean pharmacokinetic parameter values after a single i.v. dose of A77 1726 were distribution (A) and elimination (B) intercepts (15.2 μg/mL and 34.5 μg/mL, respectively), distribution and elimination half-lives (1.5 and 71.8 h, respectively), area under the curve (AUC0∞; 3723 μg*h/mL), mean residence time (MRT; 93 h), clearance (Clobs; 1.1 mL/kg/h), and volume of distribution at steady state (Vdss; 97 mL/kg). Mean pharmacokinetic parameter values after a single oral dose of leflunomide were absorption and elimination rate constants (0.3 1/h and 0.01 1/h, respectively), absorption and elimination half-lives (2.3 and 59.1 h, respectively), AUC0∞ (3966 μg*h/mL), and maximum observed plasma concentration (Cmax; 38 μg/mL). The bioavailability after a single oral dose of leflunomide was 100%. The mean ± SD A77 1726 concentration that inhibited 50% lymphocytes (EC50) was 16 ± 13.5 μg/mL. The mean ± SD maximum A77 1726 concentration (ECmax) was 61.0 ± 23.9 μg/mL.

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.

Nile tilapia Oreochromis niloticus were medicated with florfenicol (AQUAFLOR type A medicated article; Schering-Plough Animal Health, Summit, New Jersey) via a medicated ration at 15 mg florfenicol x kg fish body weight(-1) d(-1) for 10 d to compare the elimination kinetics of the test article in different size fish held at 25 degrees C. The groups of fish used in the study had mean weights of approximately 100, 250, and 500 g. In each trial, the fish were provided the medicated ration and 15 fish were processed at each of seven time points postfeeding for determination of the florfenicol concentration in serum and the florfenicol residue in the edible portion (composite muscle and skin). There was a trend toward shorter half-lives of elimination in the smaller fish. The elimination times in muscle-skin (times to reach the established tolerance concentration for channel catfish Ictalurus punctatus and salmonids of 1.0 microg florfenicol residue/g) and half-lives were 9.2 and 1.2 d (100 g), 8.6 and 1.7 d (250 g), and 12.7 and 2.2 d (500 g), respectively.

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 drug's rapid terminal half-life indicated that published dosing intervals for birds may be inadequate in RTHs and GHOs.

The recently recognized potential of sodium chlorate as a possible preharvest food safety tool for pathogen reduction in meat animals has spurred interest in the pharmacokinetics of intraruminally dosed chlorate. Six Loala cattle were assigned (one heifer and one steer per treatment) to one of three intraruminal doses of radiolabeled sodium [36Cl]chlorate (21, 42, or 63 mg/kg body weight) administered in four equal aliquots over a 24-h period. Blood and serum were collected (29 samples in 48 h). Total radioactive residues were measured and the radioactive moieties were speciated. Chlorate appeared rapidly in blood and serum after dosing. For animals administered a dose of 42 or 63 mg/kg, the half-life of absorption was estimated at 0.6-0.9 h. Serum chlorate concentrations progressively increased with aliquot administration until peaking at 6-21 parts per million at 26 h. Between aliquot administrations, serum chlorate levels typically peaked in 3.5 h or less. The half-life of chlorate elimination ranged between 6.9 and 11 h, depending on the dose. Ultimately, absorption of chlorate removes it from its desired site of action, the lower gastrointestinal tract, thereby reducing its efficacy. Further research is needed to develop a chlorate formulation that will allow passage to the lower gastrointestinal tract.

In vitro putative cytochrome P450 3A mediated activity, and inhibition thereof, were measured in four avian species using midazolam (MDZ) as a substrate and ketoconazole as an inhibitor. All species produced 1-hydroxymidazolam (1-OH MDZ) to a much greater extent than 4-hydroxymidazolam (4-OH MDZ). Calculated Vmaxapparent values for formation of 1-OH MDZ were 117 ± 17, 239 ± 108, 437 ± 168, and 201 ± 55 pmol/mg protein*min and Kmapparent values were 2.1 ± 0.8, 2.4 ± 1.6, 6.7 ± 5.1 and 3.2 ± 2.1 μ [smallcapital m] for chicken, turkey, pheasant and bobwhite quail, respectively. For the formation of 4-OH MDZ the Vmaxapparent values were 21 ± 10, 94 ± 46, 144 ± 112, and 68 ± 30 pmol/mg protein*min and Kmapparent values for 4-OH MDZ formation were 12.4 ± 10.1, 18.0 ± 10.8, 38.6 ± 34.7 and 29.1 ± 10.1 μ [smallcapital m] for chicken, turkey, pheasant and bobwhite quail, respectively. In all four species, ketoconazole inhibited the production of both major metabolites of MDZ, with 4-OH MDZ formation more sensitive to inhibition than 1-OH MDZ. Pheasant and bobwhite quail appeared most sensitive to ketoconazole inhibition.

The purpose of this study was to determine whether Japanese quail (Coturnix japonica) would serve as a pharmacokinetic animal model for two small companion parrots: cockatiels (Nymphicus hollandicus) and Poicephalus parrots. Oxytetracycline (OTC) was the pharmacologic agent chosen for this study as it is eliminated primarily by renal glomerular filtration and undergoes minimal metabolism. A single intravenous injection of 20 mg/kg oxytetracycline hydrochloride was administered to the three study groups and blood samples were obtained at 5, 10, 15, and 30 min post-OTC injection as well as 1, 2, 4, 8, 12 and 24 h post-OTC injection. Quantification of plasma OTC was accomplished using a standardized microbial inhibition assay. Naïve-pooled data (NPD) analysis of the plasma concentration-time profile of OTC best fit a two-compartment open model for all three avian species. Noncompartmental analysis of the mean data yielded the following parameters for quail, cockatiels and Poicephalus parrots respectively: lambda(z) = 3.14, 4.57, 3.71 h; AUC = 38.9, 42.7, 49.6 microg x h/mL; and Cl = 514, 468, 403 mL/h/kg. Based on the similarity of these pharmacokinetic parameters, it appears that quail could be used as a model species to predict the appropriate OTC dosing regimen for small psittacine birds. A bootstrap procedure was also applied to these sparse data sets for both compartmental and noncompartmental analysis. The bootstrap procedure allowed for the calculation of variability of parameters; however, the estimates of the parameters were very similar to those calculated using the NPD and the data mean values.

The formulation of a drug can have profound effects on tissue residues and, consequently, withdrawal times (WDTs) in food animal species. The WDT is the time after completion of treatment needed for tissue concentrations of the drug and any metabolites to decrease to less than the tolerance value or drug concentrations considered safe for human consumption. A drug can have a zero WDT if, after administration, the concentrations in the tissues are less than the tolerance value. A more thorough review of WDTs and tolerances and how they are determined has been published. 1

Pharmacokinetics of ketoprofen have been established in numerous mammalian species; however, no published pharmacokinetic data exist for avian species, although some studies have evaluated the pharmacodynamics (Machin et al., 2001) and analgesic effects (Machin & Livingston, 2002) of this nonsteroidal anti-inflammatory drug in ducks. Ketoprofen is a chiral compound that exists as two enantiomers, R()) and S(+) ketoprofen. Products approved for clinical use in both human and veterinary medicine are the racemic mixtures (50:50) of the two enantiomers. Dosage regimens for birds are extrapolated from those of small mammals, although there are anatomic and metabolic differences between avian species and mammals that make extrapolation of drug dosages dangerous (Dorrestein, 1992). In addition, even if dosages for birds were available, extrapolation within the Aves class could potentially be problematic since a previous study comparing pharmacokinetic parameters for nonsteroidal anti-inflammatory drugs reported avian species differences (Baert & DeBacker, 2003). Another concern regarding the use of nonsteroidal anti-inflammatory drugs is that toxic effects may be seen at therapeutic concentrations (MacAllister et al., 1993). This has been demonstrated clinically in male Eider ducks where ketoprofen has been reported to be lethal (Mulcahy et al., 2003). For all of the aforementioned reasons, pharmacokinetic studies are important to determine appropriate therapeutic dosages for avian species. The objective of this study was to establish the pharmacokinetics of intravenous, intramuscular, and orally administered ketoprofen in adult Japanese quail, a popular laboratory animal avian species. A three-period cross-over design was used so that each adult domestic Japanese quail (Coturnix japonica; n 1⁄4 45) received ketoprofen (2 mg/kg) intravenously, intramuscularly, or orally. The average body weight of the birds was 146 g (±26). Twoweek intervals were allowed between each period of the study. No remarkable findings were found on physical examination. Food and water were provided ad libitum throughout the study. The University of California, Davis, Animal Care and Use Committee approved this study. In period 1, quails 1–15 were administered ketoprofen (Ketofen, Fort Dodge, Iowa 50501, USA; 2 mg/kg) intravenously via the right jugular vein; quails 16–30 received ketoprofen (2 mg/kg) intramuscularly in the pectoral muscle; and quails 31–45 received ketoprofen (2 mg/kg) orally via ingluvial gavage. To ensure accurate dosing, the commercial ketoprofen solution was diluted with sterile 0.9% NaCl and administered immediately after dilution. In periods 2 and 3, treatments were altered so that each route of drug administration was delivered in sequence. Blood samples (0.5 mL/sample) were collected from the right jugular vein 1 week prior to drug administration (time 1⁄4 0) and at times 0.08, 0.17, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, and 8 h following drug administration. Following ketoprofen administration, a maximum of two 0.5 mL blood samples per bird were drawn so that the total volume of blood drawn from each bird did not exceed 1% of the body weight. Blood samples were collected into microtainer tubes containing heparin and centrifuged at 2000 g for 10 min. The plasma was decanted, labeled, and frozen at )20 C until the assays were performed. Ketoprofen concentrations in test plasma for the pharmacokinetic portion were measured using liquid chromatography – mass spectrometry (LC-MS) analysis of protein-precipitated plasma samples (Skinner et al., 2004). Plasma calibrators were prepared by diluting working ketoprofen solutions with drug-free quail plasma to concentrations of 0.01, 0.05, 0.1, 0.25, 0.5, 0.75, 1.0, 2.0, 4.0, 8.0, 16.0, and 32 lg/mL. Quality control (QC) samples (plasma fortified with analytes at concentrations mid-point of the standard curve) were also included. Each sample’s concentration of ketoprofen was determined by the J. vet. Pharmacol. Therap. 28, 399–402, 2005. SHORT COMMUNICATION

Avian aspergillosis is commonly treated with itraconazole (ITZ). This paper describes two studies using mallard ducks (Anas platyrhynchos). The first study evaluated in vivo release of ITZ from subcutaneously injected controlled-release gel formulations and the second study compared pharmacokinetic parameters for two ITZ oral suspensions. ITZ-A suspension was prepared by mixing contents of commercially available capsules with hydrochloric acid and orange juice. ITZ-B suspension was prepared by dispersing the complex of the drug with hydroxypropyl-beta-cyclodextrin in water. Concentrations of ITZ and its active metabolite, hydroxyitraconazole (OH-ITZ), in plasma and tissue samples were measured using high-performance liquid chromatography. In the second study, drug concentrations in plasma samples were also analyzed using a bioassay. After administration of two ITZ controlled-release formulations, plasma and tissue concentrations of ITZ and OH-ITZ were either very low (< or = 52 ng/mL) or undetectable. Exceptions included skin, subcutaneous fat, and muscle adjacent to the injection site. The drug from ITZ-A and ITZ-B suspensions was absorbed after oral administration. ITZ pharmacokinetic parameters for both suspensions in mallard ducks were similar and the bioassay successfully measured ITZ equivalents in plasma samples from ducks.

1Because there is little economic incentive for pharmaceutical companies to pursue antidote approval for a limited market, it is unlikely that this situation will change in the near future. In most instances, practitioners seeking to treat food animals for toxicoses are compelled to either use products in an extralabel manner or to compound antidotes from bulk sources. There are relatively few data from which scientifically based withdrawal intervals (WDIs) may be developed for the protection of human health. This Food Animal Residue Avoidance Databank (FARAD) Digest provides a summary of regulatory and scientific information regarding the most commonly recommended antidotes used in food animals. None of the drugs covered in this digest have been approved by the FDA Center for Veterinary Medicine (FDA/CVM) as New Animal Drugs. The information on residues presented in this digest is for the antidotes, not for the toxicants. When an antidote must be used to treat a food animal for a toxicosis, a WDI to ensure depletion of the toxicant is also required, and it may be longer than the WDI for the antidote. FARAD can provide WDI recommendations for a wide range of toxicants; however, these recommendations must be made on a case-by-case basis because of differences in exposure route, dose, and duration. Unapproved Veterinary Antidotes Marketed with Veterinary Labels The FDA/CVM has applied regulatory discretion and does not prohibit the commercial manufacture and marketing of several veterinary antidotes. These products do not have New Animal Drug Approval (NADA) numbers and have not been formally approved by the FDA/CVM. These products are manufactured under Good Manufacturing Practices, and their labels are reviewed and on file with the FDA/CVM. They may be used as antidotes in food animals, although higher dosages or more prolonged treatment than that indicated on the labels may be necessary. Animal Medicinal Drug Use Clarification Act requirements do not apply to these drugs because they are not approved drugs; however, veterinarians are strongly encouraged to follow AMDUCA requirements when using these drugs. 2

Objective—To investigate the feasibility of using multivariate cluster analysis to meta-analyze pharmacokinetic data obtained from studies of pharmacokinetics of ampicillin trihydrate in cattle and identify factors that could account for variability in pharmacokinetic parameters among studies.Sample Population—Data from original studies of the pharmacokinetics of ampicillin trihydrate in cattle in the database of the Food Animal Residue Avoidance Databank.Procedure—Mean plasma or serum ampicillin concentration versus time data and potential factors that may have affected the pharmacokinetics of ampicillin trihydrate were obtained from each study. Noncompartmental pharmacokinetic analyses were performed, and values of pharmacokinetic parameters were clustered by use of multivariate cluster analysis. Practical importance of the clusters was evaluated by comparing the frequency of factors that may have affected the pharmacokinetics of ampicillin trihydrate among clusters.Results—A single cluster with lower mean values for clearance and volume of distribution of ampicillin trihydrate administered PO, compared with other clusters, was identified. This cluster included studies that used preruminant calves in which feeding was withheld overnight and calves to which probenecid had been administered concurrently.Conclusions and Clinical Relevance—Meta-analysis was successful in detecting a potential subpopulation of cattle for which factors that explained differences in pharmacokinetic parameters could be identified. Accurate estimates of pharmacokinetic parameters are important for the calculation of dosages and extended withdrawal intervals after extralabel drug administration. (Am J Vet Res2005;66:108–112)

Residues of oxytetracycline (OTC) in serum, liver, and muscle–skin were measured in sunshine bass (female white bass Morone chrysops × male striped bass M. saxatilis), Nile tilapia Oreochromis niloticus, summer flounder Paralichthys dentatus, and walleyes Sander vitreus (formerly Stizostedion vitreum). These studies were conducted to compare the time for OTC concentrations to fall below 2.0 μg/g (the current tolerance set by the U.S. Food and Drug Administration (USFDA)) among fish species representing various culture conditions of freshwater and salt water as well as different temperature niches. The sum of mean tissue OTC concentration plus two standard deviations in the edible portion (muscle plus skin) of all fish was below 2.0 μg/g at 11 d postdosing. When possible, depletion data were fitted to a one-compartment pharmacokinetic model. Although temperature niche did not appear to consistently affect residue depletion within species, the warmwater species (sunshine bass and Nile tilapia) ofte...

Investigators frequently face the quandary of how to interpret the often times disparate pharmacokinetic parameter values reported in the literature. Combining of data from multiple studies (meta-analysis) is a useful tool in pharmacokinetics. Few studies have explored the use of meta-analysis for veterinary species. Even fewer studies have explored the potential strengths and weaknesses of the various methods of performing a meta-analysis. Therefore, in this study we performed a meta-analysis for oxytetracycline (OTC) and procaine penicillin G (PPG) given intramuscularly to cattle. The analysis included 28 individual data sets from 18 published papers for PPG (288 data points), and 41 individual data sets from 25 published papers for OTC (489 data points). Three methods were used to calculate the parameters. The first was a simple statistical analysis of the parameter values reported in each paper. The second method was a standard Two-Stage Method (TSM) using the mean concentration vs. time data extracted from each paper. The third method was the use of nonlinear mixed effect modeling (NMEM) of the concentration vs. time data reported in the various papers, treating the mean data as if each set came from an individual animal. The results of this evaluation indicate that all three methods generate comparable mean parameter estimates for OTC and PPG. The only significant difference noted was for OTC absorption half-lives taken from the published literature, a difference attributable to the use of an alternative method of parameter calculation. The NMEM procedure offers the possibility of including covariates such as dose, age, and weight. In this study the covariates did not influence the derived parameters. A combination approach to meta-analysis of published mean data is recommended, where the TSM is the first step, followed by the NMEM approach.

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.

Pharmacokinetic studies of antibiotics in South American camelids are uncommon, therefore drugs are often administered to llamas and alpacas based on dosages established in other domestic species. The disposition of ceftiofur sodium was studied in llamas following intramuscular administration and in alpacas following intravenous and intramuscular administration. Eleven adult llamas were given ceftiofur sodium by intramuscular injection. Each animal received either a standard dose of 2.2 mg/kg or an allometrically scaled dose ranging from 2.62 to 2.99 mg/kg in a crossover design. Ten adult alpacas were given ceftiofur sodium by intravenous and intramuscular injections. Each animal received a standard dosage of 1 mg/kg or an allometrically scaled dose ranging from 1.27 to 1.44 mg/kg i.v., and 1.31-1.51 mg/kg i.m. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, and 72 h after administration of the ceftiofur. Pharmacokinetic parameters of ceftiofur in llamas and alpacas were similar following i.m. dosing at both dose levels. The only differences noted were in the total AUC between dose levels, but the AUC/dose values were not different. A sequence effect was noted in the alpaca data, which resulted in lower AUCs for the second dose when the i.v. dose was given first, and with higher AUCs for the second dose when the i.m. dose was given first. Overall, ceftiofur pharmacokinetics in llamas and alpacas are similar, and also very similar to reported parameters for sheep and goats.

JAVMA, Vol 224, No. 4, February 15, 2004 F the purpose of this FARAD Digest, small ruminants are considered to include sheep, goats, deer, and camelids. In the United States, the small ruminant population is low, and they are all considered minor species under the Food, Drug, and Cosmetics Act (Table 1). Minor species are defined by exclusion from major species (ie, cats, dogs, horses, swine, cattle, chickens, and turkeys). In the United States, sheep were only considered to be minor species in regard to efficacy and target animal safety requirements and remained a major species when human food safety was being evaluated. This exception was attributed to the high consumption of lamb and mutton at the time of the original classification in 1983. It was not until August 2002 that the sheep drug approval process was amended so that sheep were reclassified as a minor species with regard to human food safety requirements. Classification as a minor species allows the FDA flexibility in permitting new drug applications when FARAD Digest

Twelve adult female red deer (Cervus elaphus) were given 250 mg of ceftiofur sodium by intramuscular injection (i.m.) and ballistic implant in a crossover design. Blood samples were taken from an in-dwelling jugular catheter prior to drug administration and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, and 72 h postadministration of the drug. Samples were centrifuged and plasma kept frozen at -70 degrees C until analysis for ceftiofur and active metabolites using an HPLC method. The pharmacokinetics of ceftiofur and metabolites after i.m. dosing and following ballistic implant were quite different. Absorption after i.m. injection was rapid; whereas following ballistic implant there was a lag-time until concentrations were detectable in plasma. The maximum concentration reached in plasma was higher following injection compared with ballistic implant, however the AUC calculated after ballistic implant was almost identical to the mean AUC found after i.m. dosing. The results indicate that i.m. administration of ceftiofur maintains adequate plasma levels for most susceptible bacterial pathogens for at least 12 h; therefore twice daily administration is needed in red deer. Ballistic implants produced plasma concentrations above the MIC for most bacterial pathogens from 4 to 24 h in most animals after administration; however, absorption of the drug was variable and some did not maintain effective concentrations for more than a few hours. Ceftiofur is a useful drug in red deer and twice daily i.m. administration dosing should allow treatment for susceptible bacterial pathogens.

The aim of this study was to evaluate the disposition of cyclosporine after intravenous (i.v.) and oral administration and to evaluate single sampling times for therapeutic monitoring of cyclosporine drug concentrations in cats. Six adult male cats (clinically intact) were used. Two treatments consisting of a single i.v. cyclosporine (1 mg/kg) and multiple oral cyclosporine (3 mg/kg b.i.d p.o. for 2 weeks) doses. Whole blood cyclosporine concentrations were measured at fixed times by high performance liquid chromatography and pharmacokinetic values were calculated. Mean values for the i.v. data included AUC (7413 ng/mL.h), t1/2 distribution and elimination (0.705 and 9.7 h, respectively), Cmax (1513 ng/mL), and Vd(ss) (1.71 L/kg). Mean values for the oral data included AUC (6243 ng/mL.h), t1/2 of absorption and elimination (0.227 and 8.19 h, respectively), and Cmax (480.0 ng/mL). Bioavailability of orally administered cyclosporine was 29 and 25% on days 7 and 14 respectively. Whole blood comment cyclosporine concentration 2 h after administration (C2) better correlated with AUC on days 7 and 14 than trough plasma concentration (C12). The rate of oral cyclosporine absorption was less than expected and there was substantial individual variation. Therapeutic drug monitoring strategies for cyclosporine in cats should be re-evaluated.

A physiologically based pharmacokinetic model (PBPK) for oxytetracycline (OTC) residues in sheep was developed using previously published data from a combined serum pharmacokinetic and tissue residue study [Craigmill et al. (2000) J. Vet. Pharmacol. Ther. 23, 345]. Physiological parameters for organ weights and tissue blood flows were obtained from the literature. The tissue/ serum partition coefficients for OTC were estimated from the serum and tissue residue data obtained at slaughter. The model was developed to include all of the tissues for which residue data were available (serum, kidney, liver, fat, muscle and injection site), and all of the remaining tissues were combined into a slowly perfused compartment with low permeability. Total body clearance of OTC calculated in the previous study was used as the starting value for clearance in the PBPK model, with the kidney being the only eliminating organ. The model was built using ACSL (Advanced Continuous Simulation Language) Graphic Modeler®, and the model was fit to the serum and tissue data using the ACSL Math/Optimizer® software (AEgis Technologies Group, Inc., Huntsville, AL, USA). A sensitivity analysis was also performed to determine which parameters had the greatest effect on the goodness of fit. Numerous strategies were tested to model the injection site, and a model providing a biexponential absorption of the drug from the injection bolus gave the best fit to the experimental data. The model was validated using the clearance parameters calculated from the traditional pharmacokinetic model for each individual animal in the PBPK model. This simple PBPK model well predicted OTC residues in sheep tissues after intramuscular dosing with a long-acting preparation and may find use for other species and other veterinary drugs.

Separate groups of goats were used to determine drug depletion patterns in serum (n=10), tissue (n=20) and milk (n=8) following a single intramuscular (i.m.) dose of 20 mg/kg of a long-acting oxytetracycline (OTC) formulation (Liquamycin LA-200). Milk residues were also determined following a subcutaneous (s.c.) administration of the same product at the same dose. Serum samples were taken for 24 h post-treatment and tissues (fat, liver, kidney, muscle and injection site) collected at 4, 7, 14, 21 and 28 days following injection. Milk from lactating goats was collected every 12 h for 8 days following both the i.m. and s.c. treatments utilizing an intervening 5-week washout period. Residues in serum and tissue were measured using a microbial inhibition assay, while milk residues were measured using both a microbial inhibition assay and a validated HPLC method. The serum pharmacokinetic parameters of OTC in goats were determined, with a mean AUC=67.4 microg h/mL, mean terminal half-life=14.4 h, and apparent clearance=0.33 L/kg h. Tissue half-lives could not be determined with confidence because the collection times provided only two points at which residues could be measured for most tissues. Oxytetracycline residues in all goat tissue samples measured less then cattle tissue tolerance by 96 h postdosing. One-compartment model describing milk depletion data for i.m. and s.c. dosing had terminal slope half-lives of 20.1 and 36.1 h, respectively. By 96 h post-treatment none of the milk samples contained OTC residues in excess of the cattle milk tolerance (0.3 p.p.m.). For both milk and tissue, the upper-bound 99% confidence intervals for the samples taken from goats 96 h postdosing were lower than approved cow milk and tissue tolerances.

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 microg/ml and 221 microg/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 microg x hr/ml in the hawks and 444 +/- 104 microg x 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 microg/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.

Twelve (12) lactating dairy goats (46-71 kg body wt at study initiation) were divided 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 2-week washout between injections. After another 2-week washout period, the goats were dosed with ceftiofur sodium i.m. for 5 consecutive days at either 1.1 or 2.2 mg CFAE/kg. The goats from the 2.2 mg/kg multiple dose group were dried off and the i.v. kinetic study repeated. After all injections, blood samples were obtained serially for determination of combined serum concentrations of ceftiofur and metabolites. After intravenous doses of 1.1 and 2.2 mg/kg, the harmonic means of the terminal phase half-lives were 171.8 and 233 min, respectively, for lactating does. The harmonic mean of the terminal phase half-life after an i.v. dose of 2.2 mg/kg in non-lactating does was 254 min. The AUC0-infinity was significantly less and the clearance significantly greater during lactation. After i.m. doses of 1.1 and 2.2 mg/kg, the harmonic mean terminal phase half-lives were 163 and 156 min, respectively. The i.m. bioavailability of ceftiofur sodium in goats was 100%, and the AUC0-infinity was dose-proportional from 1.1-2.2 mg CFAE/kg body weight. After five daily i.m. doses of ceftiofur sodium at either 1.1 or 2.2 mg CFAE, there was minimal accumulation of drug in serum as assessed by Cmax, and serum concentrations were dose-proportional after the multiple dosing regimen.

xtralabel intramammary administration of drugsoccurs with some regularity in dairy cattle, mostcommonly in association with mammary gland infec-tions (mastitis) that fail to respond to approved prod-ucts. To comply with AMDUCA regulations, extralabeldrug use must include a sufficiently extended with-drawal interval so that no residues are found in meat ormilk products. This is particularly important whenusing products via intramammary administrationbecause milk residue violations can have serious eco-nomic consequences for the producer and veterinarian.For some of the drugs listed in this report, well-con-ducted pharmacokinetic studies have been performedto define appropriate withdrawal intervals after intra-mammary administration in cattle, whereas for others,the recommendations may have been formulated onthe basis of limited data. To ensure food safety andavoid residue violations, it is extremely important forveterinarians to maintain good records and followextended withdrawal intervals when using intramam-mary administration of drugs in an extralabel manner.Producers should also be requested to test milk sam-ples from treated cows with an appropriate rapidresidue screening assay when a drug residue might bepresent. CeftiofurCeftiofur sodium

Six Columbia and mixed-breed sheep (three rams and three females, 33-44 kg) were euthanatized 12 h after the last of 5 intramuscular doses at 2.2 mg of [ 14 C]ceftiofur sodium/kg of body weight. Total dose accountability was 103.5 ± 4.5% : 92.55 ± 4.10% in urine, 6.53 ± 0.85% in feces, 2.40 ± 0.14% in the carcass, and 0.69 ± 0.32% in the intestinal tract. Kidneys were the tissues with highest residue concentration (9.016 ± 1.153 μg/g, 0.29% of the dose). Most residues found in kidney and liver were associated with macromolecules (95.7% and 90.5%, respectively). Of the free residues, all corresponded to polar metabolites devoid of the β-lactam ring necessary for biological activity. Desfuroylceftiofur (DFC)-dimer was the most abundant metabolite (47.58%) found in urine. Polar metabolites devoid of a β-lactam ring comprised 38.5% of the total residues. In plasma, DFC was conjugated to albumin. Free residues containing an intact β-lactam ring were not found. [ 14 C]-Ceftiofur itself was never found in the excreta or plasma or as a tissue residue.

The pharmacokinetics and pharmacodynamics of A77 1726 and leflunomide after intravenous (i.v.) and oral (p.o.) administration were evaluated in adult cats. Three treatments were administered: a single i.v. dose of A77 1726 (4 mg/kg), a single oral dose of leflunomide (4 mg/kg), and multiple oral doses of leflunomide (2 mg/kg). Mean pharmacokinetic parameter values after a single i.v. dose of A77 1726 were distribution (A) and elimination (B) intercepts (15.2 μg/mL and 34.5 μg/mL, respectively), distribution and elimination half-lives (1.5 and 71.8 h, respectively), area under the curve (AUC(0 → ∞); 3723 μg*h/mL), mean residence time (MRT; 93 h), clearance (Cl(obs); 1.1 mL/kg/h), and volume of distribution at steady state (Vd(ss); 97 mL/kg). Mean pharmacokinetic parameter values after a single oral dose of leflunomide were absorption and elimination rate constants (0.3 1/h and 0.01 1/h, respectively), absorption and elimination half-lives (2.3 and 59.1 h, respectively), AUC(0 → ∞) (3966 μg*h/mL), and maximum observed plasma concentration (C(max); 38 μg/mL). The bioavailability after a single oral dose of leflunomide was 100%. The mean ± SD A77 1726 concentration that inhibited 50% lymphocytes (EC(50) ) was 16 ± 13.5 μg/mL. The mean ± SD maximum A77 1726 concentration (EC(max)) was 61.0 ± 23.9 μg/mL.

Author(s): Forero, Larry; Nader, Glenn; Craigmill, Arthur; Ditomaso, Joseph M; Puschner, Birgit; Maas, John | Abstract: Horses, goats, sheep, and cattle can sicken or die if they eat from a poisonous plant. The best strategy is just to keep these plants out of reach. Here are photos, ID info, and poisoning symptoms for more than 30 hazardous ornamental and range plants.

Author(s): Craigmill, Arthur; Harivandi, Ali | Abstract: Lead is a heavy metal that occurs in all soils but can reach hazardous levels in some soils as a result of leaded-fuel exhaust, industrial wastes and other causes. Learn how to test your soil for safety and see what you can do if lead levels run too high.

Nile tilapia Oreochromis niloticus, walleye Sander vitreus, and hybrid striped bass (female white bass Morone chrysops x male striped bass M. saxatilis) were medicated with florfenicol (AQUAFLOR type A medicated article; Schering-Plough Animal Health, Summit, New Jersey) via a medicated ration of 10 mg florfenicol x kg fish body weight(-1) d(-1) for 10 d to compare the elimination kinetics of the test article. This study was part of a larger effort in support of a species grouping concept that could contribute to the regulatory approval process for therapeutic compounds for cultured fishes. The trials in this study were conducted at the ideal water temperature for each species and at the temperature 5 degrees C lower than the ideal. The test temperatures were 30 degrees C and 25 degrees C for Nile tilapia, 25 degrees C and 20 degrees C for both walleyes and hybrid striped bass. In all cases, the elimination kinetics of florfenicol were more rapid at higher temperatures. The time to reach the tolerance of 1 microg/g in muscle-skin, as set by the U.S. Food and Drug Administration for channel catfish Ictalurus punctatus and salmonids, ranged from 6.1 to 4.1 d for Nile tilapia, from 12.6 to 9.7 d for walleyes, and from 2.6 to 0.7 d for hybrid striped bass at temperatures between 20 degrees C and 30 degrees C.

Medaka ( Oryzias latipes ) embryo and larval short-term bioassays were used to rapidly demonstrate changes in toxicity of aqueous soil extracts at a pesticide disposal site before and after bioremediation. By chemical analysis, concentrations of most pesticides (particularly endosulfans) decreased after the 63-day bioremediation. In static larval assays of extracts before bioremediation, concentrations from 2.2 to 2.9% produced 50% larval mortality after 72 h exposure, whereas extract concentrations of 18 to 34% were required after remediation. Extract concentrations required to inhibit normal embryo development increased from 10% before bioremediation to 20% afterwards. Aqueous extracts from untreated soil were nonmutagenic (Ames bioassay) and, nine months after a 72-h exposure, were associated with no histopath-ologic alterations. Advantages inherent with medaka embryo and larval bioassay indicate that fish-based biomonitoring might significantly improve efforts to characterize hazardous waste sites.

The enantioselective pharmacokinetics of single dose (2 mg/kg) racemic carprofen (CPF) were evaluated in adult New Zealand white rabbits after intravenous (i.v.) and subcutaneous (s.c.) dose. Six rabbits were utilized in a two-way randomized crossover study and serial blood samples were collected. Plasma CPF concentrations were determined by high-performance liquid chromatography. After i.v. and s.c. racemic CPF administration, plasma concentration-time curves were best described by a two-compartment open model and a one-compartment model, respectively. The S(+) CPF enantiomer predominated in plasma following both routes of administration. Mean observed clearance of R(-)-CPF (82.17 +/- 13.70 mL/h.kg) was more rapid than for S(+)-CPF (27.92 +/- 7.07 mL/h.kg; P0.001). T(1/2)lambda z was shorter for R(-)-CPF than S(+)-CPF after both i.v. (1.03 and 2.99 h, respectively) and s.c. (1.94 and 4.14 h, respectively) dosing. Mean AUC(0--infinity) ratios for R(-):S(+)-CPF were approximately 1:3 for both routes of administration. Mean residence time of R(-)-CPF was shorter than of S(+)-CPF (1.06 +/- 0.29 h, 3.45 +/- 0.50 h; P0.001) and R(-)- and S(+)-CPF volumes of distribution at steady state were 85.00 +/- 14.42 and 94.39 +/- 18.66 mL/kg, respectively after i.v. administration. The mean s.c. bioavailability [F (%)] for both R(-)- and S(+)-CPF was high, 94.4 +/- 22.8 and 91.0 +/- 35.7%, respectively.

Nile tilapia Oreochromis niloticus, summer flounder Paralichthys dentatus, and walleyes Sander vitreus were treated with Romet-30 (PHARMAQ AS, Oslo, Norway) via a medicated ration at 50 mg Romet-30 kg fish body weight(- 1) d(-1) for 10 d to compare the elimination kinetics of the test substance. This study was part of a larger effort to develop a species grouping concept for the labeling of therapeutic compounds for cultured fishes. The fish tests were conducted at the ideal water temperature for each species and at 5 degrees C lower than the ideal temperature except for summer flounder, which would not feed at the lower temperature of 15 degrees C. Test temperatures were 30 degrees C and 25 degrees C for Nile tilapia, 20 degrees C and 17 degrees C for summer flounder, and 25 degrees C and 20 degrees C for walleyes. Neither component of Romet-30 (sulfadimethoxine and ormetoprim) could be detected in samples of the edible portion of walleyes (muscle plus skin) collected at day 10 posttreatment or thereafter. In studies with summer flounder, only one fish had a detectable concentration of either component on day 21 or thereafter. Elimination of Romet-30 by Nile tilapia was extremely rapid. The limited number of Nile tilapia with detectable sulfadimethoxine or ormetoprim during the posttreatment period prevented the determination of elimination half-life or elimination in this species.

In vivo plasma pharmacokinetics of midazolam hydrochloride (5 mg/kg i.v.) were determined in commercially raised broiler chickens, turkeys, ring-necked pheasants and bobwhite quail. Pharmacokinetic profiles of midazolam were similar for all four species, especially with regard to the area under the plasma drug concentration-time curve. Estimates of the half-life of elimination of midazolam were 0.42, 1.45, 1.90, and 9.71 h for turkeys, chickens, bobwhite quail, and pheasant, respectively. This was similar to the major metabolite (1-hydroxymidazolam). Elimination half-lives for 1-hydroxymidazolam were 1.35, 1.86, 1.97, and 13.97 h for turkey, chicken, bobwhite quail and pheasant, respectively. Elimination half-lives for 4-hydroxymidazolam were 0.76, 1.23, 2.85, and 13.82 h for chicken, turkey, pheasant, and bobwhite quail, respectively. In addition to traditional pharmacokinetic approaches to parameter estimation, a bootstrapping technique was employed to attempt to achieve more realistic approximations of the concentrations at later time-points.

Tegaserod, a serotonin agonist, has been shown to have prokinetic effects in horses, but pharmacokinetic information is not currently available. The pharmacokinetics and in vitro effects of tegaserod were evaluated. Tegaserod increased the contractile activity of smooth muscle preparations of the equine pelvic flexure. Pertinent pharmacokinetic parameters for a single IV and oral dose were determined. Therapeutic plasma concentrations of tegaserod were achieved by a single oral dose at 0.27 mg/kg. These findings indicate that further clinical studies are warranted to investigate potential benefits in cases of functional gastrointestinal motility disorders in horses.

Penicillin is one of the most commonly detected drug residues in tissues and milk, and is the antimicrobial for which information is most often sought through FARAD.