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This review provides a tutorial for individuals interested in quantitative veterinary pharmacology and toxicology and offers a basis for establishing guidelines for physiologically based pharmacokinetic (PBPK) model development and application in veterinary medicine. This is important as the application of PBPK modeling in veterinary medicine has evolved over the past two decades. PBPK models can be used to predict drug tissue residues and withdrawal times in food-producing animals, to estimate chemical concentrations at the site of action and target organ toxicity to aid risk assessment of environmental contaminants and/or drugs in both domestic animals and wildlife, as well as to help design therapeutic regimens for veterinary drugs. This review provides a comprehensive summary of PBPK modeling principles, model development methodology, and the current applications in veterinary medicine, with a focus on predictions of drug tissue residues and withdrawal times in food-producing animals. The advantages and disadvantages of PBPK modeling compared to other pharmacokinetic modeling approaches (i.e., classical compartmental/noncompartmental modeling, nonlinear mixed-effects modeling, and interspecies allometric scaling) are further presented. The review finally discusses contemporary challenges and our perspectives on model documentation, evaluation criteria, quality improvement, and offers solutions to increase model acceptance and applications in veterinary pharmacology and toxicology.

The use of an extended release ceftiofur crystalline-free acid formulation (CCFA, Excede For Swine(®) , Pfizer Animal Health) in koi was evaluated after administration of single intramuscular (i.m.) or intracoelomic (i.c.) doses. Twenty koi were divided randomly into a control group and four treatment groups (20 mg/kg i.m., 60 mg/kg i.m., 30 mg/kg i.c., and 60 mg/kg i.c.). Serum ceftiofur-free acid equivalents (CFAE) concentrations were quantified. The pharmacokinetic data were analyzed using a nonlinear mixed-effects approach. Following a CCFA injection of 60 mg/kg i.m., time durations that serum CFAE concentrations were above the target concentration of 4 μg/mL ranged from 0.4 to 2.5 weeks in 3 of 4 fish, while serum CFAE concentrations remained below 4 μg/mL for lower doses evaluated. Substantial inter-individual variations and intra-individual fluctuations of CFAE concentrations were observed for all treatment groups. Histological findings following euthanasia included aseptic granulomatous reactions, but no systemic adverse effects were detected. Given the unpredictable time vs. CFAE concentration profiles for treated koi, the authors would not recommend this product for therapeutic use in koi at this time. Further research would be necessary to correlate serum and tissue concentrations and to better establish MIC data for Aeromonas spp. isolated from naturally infected koi.

Item does not contain fulltext A common feature of human and veterinary pharmacokinetics is the importance of identifying and quantifying the key determinants of between-patient variability in drug disposition and effects. Some of these attributes are already well known to the field of human pharmacology such as bodyweight, age, or sex, while others are more specific to veterinary medicine, such as species, breed, and social behavior. Identification of these attributes has the potential to allow a better and more tailored use of therapeutic drugs both in companion and food-producing animals. Nonlinear mixed effects (NLME) have been purposely designed to characterize the sources of variability in drug disposition and response. The NLME approach can be used to explore the impact of population-associated variables on the relationship between drug administration, systemic exposure, and the levels of drug residues in tissues. The latter, while different from the method used by the US Food and Drug Administration for setting official withdrawal times (WT) can also be beneficial for estimating WT of approved animal drug products when used in an extralabel manner. Finally, NLME can also prove useful to optimize dosing schedules, or to analyze sparse data collected in situations where intensive blood collection is technically challenging, as in small animal species presenting limited blood volume such as poultry and fish.

The objective of this study was to determine the pharmacokinetics of intravenous and oral firocoxib in 10 healthy preweaned calves. Firocoxib (0.5 mg/kg) was initially administered i.v. to calves, and following a 14-day washout period, animals received firocoxib orally prior to cautery dehorning. Firocoxib concentrations were determined by liquid chromatography-tandem mass spectrometry. Changes in hematology and plasma chemistry were determined using automated methods. Computer software was used to estimate pharmacokinetic parameters best described with a two-compartment model for i.v. administration and a one-compartment model for p.o. administration. Following i.v. dosing, the geometric mean (range) T1/2K10 and T1/2β were 6.7 (4.6-9.7) and 37.2 (23.5-160.4) h, respectively, Vss was 3.10 (2.10-7.22) L/kg, and CL was 121.7 (100.1-156.7) mL/h/kg. Following oral administration, geometric mean (range) Cmax was 127.9 (102.5-151.3) ng/mL, Tmax was 4.0 (2.6-5.6) h, and T1/2K10 was 18.8 (14.2-25.5) h. Bioavailability of oral firocoxib was calculated using the AUC derived from both study populations to be 98.4% (83.1-117.6%). No adverse clinical effects were evident following firocoxib administration. Pharmacokinetic analysis of i.v. and p.o. firocoxib indicates high bioavailability and a prolonged terminal half-life in preweaned calves.

Tulathromycin, a long acting macrolide antibiotic, has demonstrated efficacy against respiratory pathogens including Mycoplasma bovis and M. hyopneumoniae. A pharmacokinetic study was performed to evaluate the clinical applicability of tulathromycin in desert tortoises following a single intramuscular dose of 5 mg/kg. A single blood sample was collected from 110 different desert tortoises at 0.25, 0.5, 1, 4, 8, 24, 48, 72, 120, and 240 h following drug administration. Plasma concentrations of the parent form of tulathromycin were measured using liquid chromatography/mass spectrometry. As each tortoise was only bled once, pharmacokinetic parameters were initially estimated using a naïve pooled data approach. Given the variability in the data, population-based compartmental modeling was also performed. Using nonparametric population compartmental modeling, a two-compartment model with first-order absorption and elimination best fit the data. An observed Cmax of 36.2 ± 29.7 μg/mL was detected at 0.25 h (observed Tmax ). The elimination half-life (T½el ) was long (77.1 h) resulting in detectable plasma concentrations 240 h postadministration. This study represents a preliminary step in evaluating the utility of tulathromycin in chelonian species and demonstrates that population data modeling offers advantages for estimating pharmacokinetic parameters where sparse data sampling occurs and there is substantial variability in the data.

The pharmacokinetics of intramuscularly administered ceftiofur crystalline-free acid (CCFA) were determined in pigs that were clinically healthy (n = 8), vaccinated with a Porcine reproductive and respiratory syndrome modified live virus (PRRS MLV) (n = 10), challenged with wild-type porcine reproductive and respiratory syndrome virus (PRRSv) VR-2385 (n = 10), or vaccinated with PRRS MLV and later challenged with wild-type PRRSv VR-2385 (n = 10). Animals were given a single dose of CCFA intramuscularly at 5 mg/kg body weight. Blood was collected at 0 (pretreatment), 0.25, 0.5, 1, 6, 12, 24, 48, 96, 144, 192, and 240 h postinjection. Plasma was analyzed using liquid chromatography-mass spectrometry. Plasma concentration–time curves for each group were evaluated with noncompartmental modeling. When compared to control animals, those receiving the PRRSv wild-type challenge only had a lower AUC0-last, higher Cl/F, and higher Vz/F. The PRRSv wild-type challenge only group had the longest T1/2λ. The Cmax did not differ among all four treatments. Control animals had no statistically significant differences from animals vaccinated with PRRS MLV alone or animals vaccinated with PRRS MLV and later challenged with wild-type PRRSv. Our results suggest that PRRSv wild-type infection has the potential to alter CCFA pharmacokinetics and PRRS MLV vaccination may attenuate those changes.

This study is part of an ongoing effort to develop animal models that provide milk and sufficient infant (offspring) plasma samples to fully describe a drug's pharmacokinetics to quantitate the risk to the nursing infant. Ciprofloxacin was administered to six healthy Holstein cows as a constant rate intravenous infusion (flow rate was weight adjusted) to achieve a steady-state concentration of approximately 300 ng/mL for 7 days. Plasma and milk samples were collected from the cow at regular intervals over the course of the 7 days. The plasma and milk samples were analyzed for ciprofloxacin by high-performance liquid chromatography. The milk was fed to calves, and calf plasma samples were analyzed to study the lactational transfer of ciprofloxacin from dam to nursing neonate. Remarkably, concentrations of ciprofloxacin in milk were 45 times higher than plasma drug concentrations in the dam. Approximately 6% of the administered dose was transferred to the milk, resulting in an average oral dose of 0.5 mg/kg to the calves with every feeding. The drug did not accumulate in the calves, and plasma concentrations were between one-tenth and one-fifth the plasma concentrations of the dam.

Lainesse, C., Gehring, R., Pasloske, K., Smith, G., Soback, S., Wagner, S., Whittem, T. Challenges associated with the demonstration of bioequivalence of intramammary products in ruminants. J. vet. Pharmacol. Therap. 35 (Suppl. 1), 65–79. This article explores the numerous challenges encountered when the goal is to demonstrate bioequivalence (BE) between test and reference intramammary (IMM) products in ruminants. Numerous pathophysiological factors of mastitis and physicochemical properties of IMM formulations are implicated in the difficulties in confirming BE for this dosage form. Advantages and disadvantages of current BE study designs are discussed, and alternative perspectives are outlined. Ongoing and future research increasing our knowledge of the pharmacokinetics and pharmacodynamics of antimicrobial drugs delivered through this route is crucial to better understanding the implications of clinically significant formulation differences in the demonstration of BE and may also help in developing more effective IMM formulations for ruminants.

Gehring, R., Martinez, M. Assessing product bioequivalence for extended-release formulations and drugs with long half-lives. J. vet. Pharmacol. Therap.35 (Suppl. 1), 3–9. When a drug product remains in the body for a duration of hours or days, estimating the extent of drug exposure is relatively straightforward. For immediate release (IR) dosage forms, the peak drug concentration (Cmax) and time to peak concentrations (Tmax) are typically adequate for comparing product rates of drug absorption. However, unique complexities need to be addressed when a drug remains in the system for a duration of months or years. Specifically, if the long duration of exposure is attributable to formulation effects, Cmax and Tmax may not be adequate to compare the rate of drug absorption, especially when there are multiphasic absorption processes. In this case, it may be appropriate to use partial (segmented areas) for comparing product profiles. However, the decision of how the curves are segmented is not straightforward. Points to consider are discussed in this manuscript. Alternatively, if the long half-life is due to the pharmacokinetics (PK) of the active pharmaceutical ingredient and not to formulation effects, Cmax and Tmax may be appropriate metrics for the rate of absorption but decisions regarding the duration of blood sampling needed to capture the AUC should be based upon an assessment of the inherent variability in drug absorption and elimination. Furthermore, it is important to be confident that the absorption phase is complete. In this manuscript, we explore some of the difficulties associated with determining optimal metrics for comparing the rate and extent of product release for long half life drugs when the long duration of exposure is attributable to either the inherent drug PK or to formulation effects.

Management of neuropathic pain in dairy cattle could be achieved by combination therapy of gabapentin, a GABA analog and meloxicam, an nonsteroidal anti-inflammatory drug. This study was designed to determine specifically the depletion of these drugs into milk. Six animals received meloxicam at 1 mg/kg and gabapentin at 10 mg/kg, while another group (n=6) received meloxicam at 1 mg/kg and gabapentin at 20 mg/kg. Plasma and milk drug concentrations were determined over 7 days postadministration by HPLC/MS followed by noncompartmental pharmacokinetic analyses. The mean (±SD) plasma C(max) and T(max) for meloxicam (2.89±0.48 μg/mL and 11.33±4.12 h) were not much different from gabapentin at 10 mg/kg (2.87±0.2 μg/mL and 8±0 h). The mean (±SD) milk C(max) for meloxicam (0.41±80.16 μg/mL) was comparable to gabapentin at 10 mg/kg (0.63±0.13 μg/mL and 12±6.69 h). The mean plasma and milk C(max) for gabapentin at 20 mg/kg p.o. were almost double the values at 10 mg/kg. The mean (±SD) milk to plasma ratio for meloxicam (0.14±0.04) was lower than for gabapentin (0.23±0.06). The results of this study suggest that milk from treated cows will have low drug residue concentration soon after plasma drug concentrations have fallen below effective levels.

Mosher, R. A., Coetzee, J. F., Cull, C. A., Gehring, R., KuKanich, B. Pharmacokinetics of oral meloxicam in ruminant and preruminant calves. J. vet. Pharmacol. Therap. 35, 373–381. The pharmacokinetics of oral meloxicam has been studied in ruminant, but not preruminant calves. Oral meloxicam was administered at 0.5 mg/kg to six ruminant calves via gavage (RG); to six preruminant calves via gavage (PRG); and to six preruminant calves via suckling in milk replacer (PRF). Plasma drug concentrations, determined over 120-h postadministration, were analyzed by compartmental and noncompartmental methods. The rate of drug absorption was faster (P

Al-Bataineh, M. M., van der Merwe, D., Schultz, B. D., Gehring, R. Molecular and functional identification of organic anion transporter isoforms in cultured bovine mammary epithelial cells (BME-UV). J. vet. Pharmacol. Therap. 35, 209–215. Mammary epithelial cells express a diversity of membrane transporters including members of organic cation and organic anion (OAT) transporter subfamilies. Four mammal OAT isoforms have been identified: OAT-1, OAT-2, OAT-3, and OAT-4. The pharmacological significance of OAT isoforms has been emphasized because of their role in the movement of a wide variety of substrates across epithelial barriers. The present study identified (molecularly and functionally) bovine OAT isoforms in bovine mammary epithelial (BME-UV) cells. mRNA expression levels of all tested transporters in BME-UV cells were less than expression levels of the corresponding transporters in bovine kidney. Directionality in the flux of P-aminohippuric acid and acetylsalicylate, compounds known to interact with OAT-1 and OAT-2, respectively, across BME-UV monolayers was not observed at the concentrations used in this study. Directionality was, however, observed in the flux of estrone sulfate (EsS). Adding probenecid, penicillin G or nonradiolabeled EsS to the apical donor compartment significantly increased the apical-to-basolateral flux of EsS across the BME-UV monolayer. These results suggest that BME-UV cells express an organic anion transport system, making it a potentially useful model to study the role of this transport system in the mammary epithelial barrier.

Bergamasco, L., Coetzee, J. F., Gehring, R., Murray, L., Song, T., Mosher, R. A. Effect of intravenous sodium salicylate administration prior to castration on plasma cortisol and electroencephalography parameters in calves. J. vet. Pharmacol. Therap. 34, 565–576. Nociception is an unavoidable consequence of many routine management procedures such as castration in cattle. This study investigated electroencephalography (EEG) parameters and cortisol levels in calves receiving intravenous sodium salicylate in response to a castration model. Twelve Holstein calves were randomly assigned to the following groups: (i) castrated, untreated controls, (ii) 50 mg/kg sodium salicylate IV precastration, were blood sampled at 0, 5, 10, 20, 30, 45, 60, 90, 120, 150, 180, 240, 360, and 480 min postcastration. The EEG recording included baseline, castration, immediate recovery (0–5 min after castration), middle recovery (5–10 min after castration), and late recovery (10–20 min after castration). Samples were analyzed by competitive chemiluminescent immunoassay and fluorescence polarization immunoassay for cortisol and salicylate, respectively. EEG visual inspection and spectral analysis were performed. Statistical analyses included anova repeated measures and correlations between response variable. No treatment effect was noted between the two groups for cortisol and EEG measurements, namely an attenuation of acute cortisol response and EEG desynchronization in sodium salicylate group. Time effects were noted for EEG measurements, cortisol and salicylates levels. Significant correlations between cortisol and EEG parameters were noted. These findings have implications for designing effective analgesic regimens, and they suggest that EEG can be useful to monitor pain attributable to castration.

Reinbold, J. B., Coetzee, J. F., Gehring, R., Havel, J. A., Hollis, L. C., Olson, K. C., Apley, M. D. Plasma pharmacokinetics of oral chlortetracycline in group fed, ruminating, Holstein steers in a feedlot setting. J. vet. Pharmacol. Therap. 33, 76–83. Chlortetracycline HCl (CTC) has impacted profitable livestock production since 1945. However, pharmacokinetic parameters for CTC in ruminating cattle are unavailable in peer-reviewed literature. A total of 18 steers were randomized to 4.4, 11, or 22 mg/kg/day p.o. CTC treatment groups (n = 6). Chlortetracycline treatment was offered as one-half of the daily dose b.i.d. (160 total doses/group) for 80 days. Blood samples were collected at selected time points throughout an 83-day study and analyzed with a solid phase extraction technique and novel ultrahigh performance liquid chromatography-mass spectroscopy/mass spectroscopy analytical method. Noncompartmental analysis (NCA) determined individual pharmacokinetic parameters by treatment group with coefficient of variation (CV %) estimates. A one-compartment open model with first order absorption and elimination, where absorption rate constant was equal to elimination rate constant, was fitted using nonlinear mixed effects modeling (NLMEM). NLMEM determined the primary pharmacokinetic parameters: volume of distribution (V/F, 40.9 L/kg) and rate constant (k, 0.0478 h−1), and the secondary parameters: dose-normalized area under the curve (AUC/D, 0.29 h·μg/L), clearance (Cl/F, 1.8 L/kg/h), elimination half-life (t1/2, 16.2 h), Cmax/Dose (4.5 ng/mL), and time of Cmax (Tmax, 23.3 h) with improved CV estimates over NCA. Dose linearity was confirmed by anova of parameters derived from NCA by treatment group. Further studies are necessary for determining absolute bioavailability and pharmacokinetic–pharmacodynamic relationships of CTC in group fed, ruminating cattle.

A pharmacokinetic and bioavailability study of spectinomycin was conducted in healthy broiler chickens following administration of a single (50 mg/kg bw) intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) dose and oral doses of 50 and 100 mg/kg bw. Following i.v. administration, the elimination half-life (t1/2beta), mean residence time (MRT), volume of distribution at steady-state (Vd(ss)), volume of distribution based on the terminal phase (Vd(z)) and total body clearance (ClB) were 1.46+/-1.10 h, 1.61+/-1.05 h, 0.26+/-0.009 L/kg, 0.34 (0.30-0.38) L/kg and 2.68+/-0.017 mL/min/kg respectively. After i.m. and s.c. dosing, the Cmax was 152.76+/-1.08 and 99.77+/-1.04 microg/mL, achieved at 0.25 (0.25-0.50) and 0.25 (0.25-1.00) h, the t1/2beta was 1.65+/-1.07 and 2.03+/-1.06 h and the absolute bioavailability (F) was 136.1% and 128.8% respectively. A significant difference in Cmax (5.13+/-0.10, 14.26+/-1.12 microg/mL), t1/2beta (3.74+/-1.07, 8.93+/-1.13 h) and ClB/F (22.69+/-0.018, 10.14+/-0.018 mL/min/kg) were found between the two oral doses (50 and 100 mg/kg bw respectively), but there were no differences in the tmax [2.00 (2.00-4.00), 2.00 (2.00-2.00) h] and Vd(z)/F [6.95 (6.34-9.06), 7.98 (4.75-10.62) L/kg). The absolute bioavailability (F) of spectinomycin was 11.8% and 26.4% after oral administration of 50 and 100 mg/kg bw respectively.

The administration of antimicrobial drugs by the intramammary route offers a convenient option for the treatment of bovine mastitis. The goal of antimicrobial treatment is to achieve effective drug concentrations at the site of infection. Drug concentrations must also decrease to safe levels before the milk is harvested for human consumption. The rate of change of drug concentrations in the milk and udder tissues over time is dependent on the physicochemical characteristics of the drug and how these interact with the biological environment, affecting the rate and extent of absorption, distribution and elimination. Studies reported in the literature have identified various pathophysiological and pharmaceutical factors that may influence these processes. This review summarizes current understanding of factors affecting the disposition of drugs following intramammary administration. Areas of incomplete knowledge requiring further research have been identified.

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

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)

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.

The objectives of this study were to determine (i) whether an association exists between individual pharmacokinetic parameters and treatment outcome when feeder cattle were diagnosed with bovine respiratory disease (BRD) and treated with gamithromycin (Zactran(®) ) at the label dose and (ii) whether there was a stronger association between treatment outcome and gamithromycin concentration in plasma or in the pulmonary epithelial lining fluid (PELF) effect compartment. The study design was a prospective, blinded, randomized clinical trial utilizing three groups of 60 (362-592 lb) steers/bulls randomly allocated within origin to sham injection or gamithromycin mass medication. Cattle were evaluated daily for signs of BRD by a veterinarian blinded to treatment. Animals meeting the BRD case definition were enrolled and allocated to a sample collection scheme consisting of samples for bacterial isolation (bronchoalveolar lavage fluid and nasopharyngeal swabs) and gamithromycin concentration determination (PELF and plasma). Gamithromycin susceptibility of M. haemolytica (n = 287) and P. multocida (n = 257) were determined using broth microdilution with frozen panels containing gamithromycin at concentrations from 0.03 to 16 μg/mL. A two-compartment plasma pharmacokinetic model with an additional compartment for gamithromycin in PELF was developed using rich data sets from published and unpublished studies. The sparse data from our study were then fit to this model using nonlinear mixed effects modeling to estimate individual parameter values. The resulting parameter estimates were used to simulate full time-concentration profiles for each animal in this study. These profiles were analyzed using noncompartmental methods so that PK/PD indices (AUC24 /MIC, AUC∞ /MIC, CMAX /MIC) could be calculated for plasma and PELF (also T>MIC) for each individual. The calculated PK/PD indices were indicative that for both M. haemolytica and P. multocida a higher drug exposure in terms of concentration, and duration of exposure relative to the MIC of the target pathogen, was favorable to a successful case outcome. A significant association was found between treatment success and PELF AUC0-24 /MIC for P. multocida. The calves in this study demonstrated an increased clearance and volume of distribution in plasma as compared to the healthy calves in two previously published reports. Ultimately, the findings from this study indicate that higher PK/PD indices were predictive of positive treatment outcomes.

A study was conducted in the Madikwe District of the North West Province to investigate the supply of veterinary medicinal products to small-scale, subsistence and emerging farmers. A combination of individual interviews, focus groups and direct observation was used to collect data. Stock remedies were made available to farmers within the district at Field Service Units that were managed by administrative staff of the Directorate of Field Services. The state veterinarian and animal health technicians were not directly involved with the sale of products. Most farmers still travelled to farmers' cooperatives in the larger centres outside the district to purchase the veterinary medicinal products they needed. Factors such as the quality of service provided, affordability and availability of required products as well as inaccessibility of outlets to all farmers contributed to the poor support of these outlets by the farmers of the district.

This study determined the impact of porcine reproductive and respiratory syndrome virus (PRRSV) and Streptococcus suis coinfection on the pharmacokinetic (PK) profile of ceftiofur hydrochloride in pigs after intramuscular (i.m.) injection. Eighteen clinically normal crossbred gilts were assigned by weight into a challenge group (10 pigs) and control group (eight pigs). Pigs in both groups received a single i.m. injection of ceftiofur hydrochloride (Excenel RTU Sterile Suspension; Zoetis) at a 5 mg/kg BW dose. Serial blood samples were collected to characterize the plasma concentration curve. After a 10 days drug washout period, the challenge group was inoculated with 2 mL of PRRSV isolate VR-2385 (10(5.75) 50% tissue culture infective doses per mL) intranasally and 8 days later inoculated S. suis. When clinical disease was evident, the second PK assessment began in both challenge and control groups. Coinfected pigs demonstrated lower values of AUC and CMAX , but higher values of Cl/F and Vz/F indicating drug kinetics were altered by infection. The data from this study have implications on ceftiofur treatment regimens in diseased pigs.

Allometric scaling is widely used for the determination of first dosage regimen and the interpolation or extrapolation of pharmacokinetic parameters across many animal species during drug development. In this article, 85 drugs used in veterinary medicine obtained from the Food Animal Residue Avoidance Databank database were selected for allometric scaling analysis. Outlier species were identified by statistical methods. The results showed that 77% and 88% of drugs displayed significant correlations between total systemic clearance (CL) and volume of distribution at steady status (Vss) vs. body weight (P

The Veterinary Pharmacovigilance Centre received 59 reports of suspected adverse drug reactions during the period January 1998 - February 2001. The number of reports received increased after the establishment of a formal procedure for recording and responding to reports. The number of reports received per species was: dogs 19, cats 15, cattle 7, sheep/ goats 6, chickens 4, pigs 3, horses 2 and giraffe 1. Many different types of adverse reactions were reported, including lack of efficacy, hypersensitivity, inappropriate use of products by non-veterinarians, known adverse effects and adverse effects encountered with extra-label use of products.

Background Dehorning is a common practice involving calves on dairy operations in the United States. However, less than 20% of producers report using analgesics or anesthetics during dehorning. Administration of a systemic analgesic drug at the time of dehorning may be attractive to dairy producers since cornual nerve blocks require 10 – 15 min to take effect and only provide pain relief for a few hours. The primary objectives of this trial were to (1) describe the compartmental pharmacokinetics of meloxicam in calves after IV administration at 0.5 mg/kg and (2) to determine the effect of meloxicam (n = 6) or placebo (n = 6) treatment on serum cortisol response, plasma substance P (SP) concentrations, heart rate (HR), activity and weight gain in calves after scoop dehorning and thermocautery without local anesthesia. Results Plasma meloxicam concentrations were detectable for 50 h post-administration and fit a 2-compartment model with a rapid distribution phase (mean T½α = 0.22 ± 0.087 h) and a slower elimination phase (mean T½β = 21.86 ± 3.03 h). Dehorning caused a significant increase in serum cortisol concentrations and HR (P Conclusions To our knowledge, this is the first published report examining the effects of meloxicam without local anesthesia on SP, activity and performance of calves post-dehorning. These findings suggest that administration of meloxicam alone immediately prior to dehorning does not mitigate signs of acute distress but may have long term physiological, behavior and performance effects.

An overview of reports of suspected adverse drug reactions received by the Veterinary Pharmacovigilance and Medicines Information Centre during the period March 2001 to February 2002 is given. A total of 77 reports were received. The majority of reports involved suspected adverse reactions that occurred in dogs and cats. Most products implicated in the reports were Stock Remedies. The products were predominantly administered either by veterinarians or trained paraveterinary professionals. Although the majority of reports were received from veterinary pharmaceutical companies, the proportion of reports received directly from veterinarians increased compared with previous years.

Objective To describe the pharmacokinetics, cortisol response and behavioral changes associated with administration of sub-anesthetic xylazine and ketamine prior to castration. Study design Prospective, randomized experiment. Animals Twenty-two male beef calves (260-310 kg). Methods Calves were randomly assigned to receive the following treatment immediately prior to surgical or simulated castration; 1) uncastrated, placebo-treated control (CONT) (n = 4), 2) Castrated, placebo treated control (CAST) (n = 6), 3) castrated with intravenous xylazine (X) (0.05 mg kg−1) (n = 6), and 4) castrated with IV xylazine (X) (0.05 mg kg−1) combined with ketamine (K) (0.1 mg kg−1) (n = 6). Blood samples collected over 10 hours post-castration were analyzed by LC-MS-MS for drug concentrations and chemiluminescent immunoassay for cortisol determination. Results Drug concentrations during the first 60 minutes post-castration fit a one-compartment open model with first-order elimination. The harmonic mean elimination half-lives (± pseudo SD) for X, X with K and K were 12.9 ± 1.2, 11.2 ± 3.1 and 10.6 ± 2.8 minutes, respectively. The proportion of the total area under the effect curve (AUEC) for cortisol during this period was significantly lower in the X group (13 ± 3%; p = 0.006) and the X+K group (14 ± 2%; p = 0.016) compared with the CAST calves (21 ± 2%). However, after 300 minutes the AUEC in the X group was higher than CAST. Significantly more calves demonstrated attitude that was unchanged from pre-manipulation behavior in the CONT (p = 0.021) and X+K treated calves (p = 0.0051) compared with the CAST calves. Conclusions Behavioral changes and lower serum cortisol concentrations during the first 60 minutes post-castration were associated with quantifiable xylazine and ketamine concentrations. Clinical relevance Low doses of xylazine and ketamine administered immediately prior to castration may offer a safe, efficacious and cost-effective systemically administered alternative or adjunct to local anesthesia.

There is ongoing concern about the potential adverse effects of xenobiotic residues in cows' milk to the human consumer. Although drugs that are intentionally administered to lactating dairy cattle are rigorously regulated to prevent harmful residues, there are numerous other potential sources of exposure that are not as easily controlled. For example, cattle may be exposed to mycotoxins, pesticides and/or persistent organic pollutants through feed, water and inhalation of polluted air. Accurate estimates of the rate and extent of excretion of these compounds into milk is important to assess the risk of exposure through cows' milk. In the present study, the expression of carrier mediated transport processes in cultured mono layers of an immortalized bovine mammary epithelial cell line (BME-UV*) was determined using a flow-through diffusion cell system, selective substrates and inhibitors of organic cation transporters (OCT†) and organic anion transporters (OAT‡). The basal to apical (BL-to-Ap§) flux of tetraethylammonium (TEA**) and estrone sulfate (ES††) significantly exceeded their flux in the opposite direction. The addition of selective inhibitors to the donor compartment significantly decreased the BL-to-Ap flux of either selective substrate. These results suggest that both OCT and OAT are functionally expressed by BME-UV cells.

The objective of this study was to evaluate the plasma pharmacokinetics of ketamine and its active metabolite norketamine administered intravenously at a dose of 0.1 mg/kg together with xylazine (0.05 mg/kg) to control the pain associated with castration in calves. A two-compartment model with an additional metabolite compartment linked to the central compartment was used to simultaneously describe the time-concentration profiles of both ketamine and its major metabolite norketamine. Parameter values estimated from the time-concentration profiles observed in this study were volume of the central compartment (V(c) = 132.82 +/- 68.23 mL/kg), distribution clearance (CL(D) = 15.49 +/- 2.56 mL/min/kg), volume of the peripheral compartment (V(T) = 257.05 +/- 41.65 mL/kg), ketamine clearance by the formation of the norketamine metabolite (CL(2M) = 8.56 +/- 7.37 mL/kg/min) and ketamine clearance by other routes (CL(o) = 16.41 +/- 3.42 mL/kg/min). Previously published data from rats suggest that the metabolite norketamine contributes to the analgesic effect of ketamine, with a potency that is one-third of the parent drug. An understanding of the time-concentration relationships and the disposition of the parent drug and its metabolite is therefore important for a better understanding of the analgesic potential of ketamine in cattle.

Objective—To evaluate plasma concentrations of substance P (SP) and cortisol in calves after castration or simulated castration. Animals—10 Angus-crossbred calves. Procedures—Calves were acclimated for 5 days, assigned to a block on the basis of scrotal circumference, and randomly assigned to a castrated or simulated-castrated (control) group. Blood samples were collected twice before, at the time of (0 hours), and at several times points after castration or simulated castration. Vocalization and attitude scores were determined at time of castration or simulated castration. Plasma concentrations of SP and cortisol were determined by use of competitive and chemiluminescent enzyme immunoassays, respectively. Data were analyzed by use of repeated-measures analysis with a mixed model. Results—Mean ± SEM cortisol concentration in castrated calves (78.88 ± 10.07 nmol/L) was similar to that in uncastrated control calves (73.01 ± 10.07 nmol/L). However, mean SP concentration in castrated calves (506.43 ± 38.11 pg/mL) was significantly higher than the concentration in control calves (386.42 ± 40.09 pg/mL). Mean cortisol concentration in calves with vocalization scores of 0 was not significantly different from the concentration in calves with vocalization scores of 3. However, calves with vocalization scores of 3 had significantly higher SP concentrations, compared with SP concentrations for calves with vocalization scores of 0. Conclusions and Clinical Relevance—Similar cortisol concentrations were measured in castrated and control calves. A significant increase in plasma concentrations of SP after castration suggested a likely association with nociception. These results may affect assessment of animal well-being in livestock production systems.

A cross-over study design was used to determine the pharmacokinetics of ampicillin in swine. Each of eight pigs was subjected to all of the following three treatments: (1) intramuscular (i.m.) injection of 17.6 mg/kg of ampicillin trihydrate; (2) injection of a mean dose of 17.6 mg/kg of ampicillin trihydrate using a needle-free (NF) injection device; and (3) intravenous injection of 17.6 mg/kg of sodium ampicillin administered as a bolus. Ampicillin trihydrate administered by NF injection in this study was not statistically different from i.m. injection as measured by AUC(0-infinity), MRT, MAT, or Cmax. However, the 90% confidence limits about the difference in NF to i.m. mean Cmax and AUC(0-infinity) values, expressed relative to the i.m. treatment mean, exceeded the traditional bioequivalence limits of +/-20%. In part, failure to demonstrate bioequivalence was attributable to small study size and the large within-subject variability associated with this drug. Therefore the power of this study was not sufficient to definitively prove or disprove bioequivalence and additional studies to describe appropriate dosage regimens for ampicillin trihydrate when administered by NF injection to pigs are warranted.

Pain associated with castration in cattle is an animal welfare concern in beef production. This study examined the effect of oral aspirin and intravenous (i.v.) sodium salicylate on acute plasma cortisol response following surgical castration. Twenty bulls, randomly assigned to the following groups, (i) uncastrated, untreated controls, (ii) castrated, untreated controls, (iii) 50 mg/kg sodium salicylate i.v. precastration and (iv) 50 mg/kg aspirin (acetylsalicylic acid) per os precastration, were blood sampled at 3, 10, 20, 30, 40, 50 min and 1, 1.5, 2, 4, 6, 8, 10 and 12 h postcastration. Samples were analyzed by competitive chemiluminescent immunoassay and fluorescence polarization immunoassay for cortisol and salicylate, respectively. Data were analyzed using noncompartmental analysis, a simple cosine model, anova and t-tests. Intravenous salicylate V(d(ss)) was 0.18 L/kg, Cl(B) was 3.36 mL/min/kg and t(1/2 lambda) was 0.63 h. Plasma salicylate concentrations above 25 microg/mL coincided with significant attenuation in peak cortisol concentrations (P = 0.029). Peak salicylate concentrations following oral aspirin administration was

The purpose of the study was to compare the disposition of pharmacologic markers for cytochrome P-450 (CYP) metabolism, glomerular filtration rate (GFR), and extracellular (ECFV) and total body fluid volumes (TBFV) of Greyhounds and Beagles. Six healthy Greyhound and six healthy Beagle dogs were studied. Antipyrine, a marker for CYP metabolism and TBFV, and inulin, a marker for the GFR and ECFV, were administered i.v. Samples were collected at predetermined times and plasma was analyzed by validated high-pressure liquid chromatography (HPLC) methods. There were no differences in the disposition or pharmacokinetic parameters for inulin between the dog breeds. However, the clearance of antipyrine (mean = 8.33 mL/min/kg) in Greyhounds was significantly slower than Beagles (13.42 mL/min/kg, P = 0.004). The volume of distribution of antipyrine was significantly larger in Greyhounds (0.789 L/kg) than in Beagles (0.644 L/kg, P = 0.01). The half-life of antipyrine was significantly longer in Greyhounds (1.09 h) compared with Beagles (0.55 h, P = 0.002). The in vitro plasma protein binding of antipyrine was significantly less in Greyhounds (28%) compared with Beagles (40.3%, P = 0.008). Greyhounds exhibited significantly slower CYP metabolism, higher TBFV, and lower in vitro protein binding of antipyrine compared with Beagles. No differences in GFR or ECFV were found.

A risk assessment of the food safety implications of drugs used in food-producing animals is an essential component of the regulatory approval process for products containing these drugs. This ensures that there is negligible risk to human health if these drugs are used according to the instructions that appear on the approved label. A relative paucity of approved products for veterinary species; however, forces veterinarians worldwide to use drugs in an extralabel manner to treat disease and alleviate suffering in animals. In food-producing animals, this may result in residues that are potentially harmful to the human consumer. This review describes how risk assessment principles can be extended to evaluate the risks posed by different classes of extralabel drug use. Risk management practices in the United States and Europe are summarized and contrasted to illustrate the application of these principles.

Rhizome extracts of Gunnera perpensa are used in traditional remedies in South Africa to treat endometritis both in humans and animals. An investigation was undertaken to determine whether this plant possesses antibacterial activity, which may explain its efficacy. Gunnera perpensa rhizome extracts were prepared serially with solvents of increasing polarity and tested for antibacterial activity. Test bacteria included the Gram-positive Enterococcus faecalis and Staphylococcus aureus and the Gram-negative Escherichia coli and Pseudomonas aeruginosa . A moderate to weak level of antibacterial activity in most of the extracts resulted, with the best minimal inhibitory concentration (MIC) value of 2.61 mg ml -1 shown by the acetone extract against S. aureus . The extracts were also submitted to the brine shrimp assay to detect possible toxic or pharmacological effects. All the extracts were lethal to the brine shrimp larvae at a concentration of 5 mg ml -1 . The acetone extract was extremely toxic at 1 mg ml -1 , with some toxicity evident at 0.1 mg ml -1 . The remainder of the extracts generally displayed little activity at concentrations lower than 5 mg ml -1 . In summary, the results indicate that although the extracts demonstrated a level of pharmacological activity, the relatively weak antibacterial activity is unlikely to justify the use of G. perpensa rhizomes in the traditional treatment of endometritis. Rather, the slightly antibacterial nature of the rhizomes may contribute to an additive effect, along with their known uterotonic activity, to the overall efficacy of the preparation.

The efficacy of a molybdate formulation and a zinc oxide bolus as prophylactic agents for enzootic icterus was evaluated in sheep. Before copper loading, liver biopsies were performed on 12 male, 6-month-old, Mutton Merino sheep to determine hepatic copper (Cu) and zinc (Zn) concentrations. The animals were restrictively randomised according to liver copper concentrations to 3 treatment groups (n = 4) to achieve similar mean liver copper concentrations per group. All sheep received 4 m /kg of a 0.5 %aqueous solution of CuSO4·5H2O intraruminally 7 days per week for 10 weeks. On Day 0 the sheep in the Mo-group were injected subcutaneously with 42 mg molybdenum (Mo) contained in a commercial molybdate formulation. The animals in the Zn-group each received a zinc oxide bolus, containing 43 g zinc oxide, via a rumen cannula. Treatment was repeated on Day 42. Four animals served as untreated controls. Urinary copper excretion, plasma copper concentration, haematocrit and glutamate dehydrogenase (GLDH) activity were determined throughout the trial. The animals were sacrificed after 10 weeks and liver samples were submitted for histopathological examination. Liver and kidney copper and zinc concentrations were determined. Neither the molybdate treatment nor the zinc oxide boluses prevented hepatic copper accumulation. The urinary copper excretion, plasma copper concentration, haematocrit and GLDH activity were not significantly different (P 0.05) from the controls.

A 4-month-old German shepherd puppy developed hindquarter weakness after vaccination with a multivalent vaccine. This is suggestive of post-vaccinal polyradiculoneuritis. To date, only 1 similar case has been reported, which may be due to the under-reporting of suspected adverse drug reactions.

Extracted from text ... Book review - Boekresensie Alternative and complementary veterinary medicine Are Simeon Thoresen 2001. Are Thoresen, Leikvollgata 31, N 3213 Sandefjord, Norway, hard cover, 544 pp., price on request from arethore@online.no, http://home.online.no/~arethor - ISBN 82 994172 2 8. This book is the 2nd edition of the original written in Norwegian. It has been translated into English by Phil Rogers MRCVS, one of Thoresen's students from Ireland. Are Simeon Thoresen graduated from the Oslo Veterinary School in 1979. Thereafter, he studied various aspects of alternative and complementary medicine, including homeopathy, acupuncture and anthroposophical medicine in various European countries as well as the USA. He uses holistic methods in his own practice. He also treats human patients ..

The objective of this study was to investigate the pharmacokinetics and tissue disposition of meloxicam after repeated oral administration in calves. Thirteen male British × Continental beef calves aged 4 to 6 months and weighing 297-392 kg received 0.5 mg/kg meloxicam per os once daily for 4 days. Plasma meloxicam concentrations were determined in 8 calves over 6 days after first treatment. Calves were randomly assigned to be euthanized at 5, 10, 15 (n = 3/timepoint), and 19 days (n = 4) after final administration. Meloxicam concentrations were determined in plasma (LOQ= 0.025 μg/mL) and muscle, liver, kidney, and fat samples (LOQ = 2 ng/g) after extraction using validated LC-MS-MS methods. The mean (± SD) Cmax , Cmin , and Caverage plasma meloxicam concentrations were 4.52 ± 0.87 μg/mL, 2.95 ± 0.77 μg/mL, and 3.84 ± 0.81 μg/mL, respectively. Mean (± SD) tissue meloxicam concentrations were highest in liver (226.67 ± 118.16 ng/g) and kidney samples (52.73 ± 39.01 ng/g) at 5 days after final treatment. Meloxicam concentrations were below the LOQ in all tissues at 15 days after treatment. These findings suggest that tissue from meloxicam-treated calves will have low residue concentrations by 21 days after repeated oral administration.