Pharmacokinetics and clinical efficacy of acetaminophen (paracetamol) in adult horses with mechanically induced lameness.

BACKGROUND: Acetaminophen has been used clinically in horses alone or combined with traditional non-steroidal anti-inflammatory drugs for treatment of musculoskeletal pain in horses. OBJECTIVES: To determine the pharmacokinetics and efficacy of acetaminophen at two doses in horses with mechanically induced lameness compared with phenylbutazone or placebo control. STUDY DESIGN: In vivo experiment. METHODS: Nine healthy mares with mechanical lameness induced via a reversible sole pressure horseshoe model were treated with acetaminophen (20 mg/kg PO; A20), acetaminophen (30 mg/kg PO; A30), phenylbutazone (2.2 mg/kg, PO; PB) and oral placebo (C) in a randomised four-way Latin square model. Plasma concentrations for A20 and A30 were analysed via LC-MS/MS and noncompartmental pharmacokinetic analysis. Heart rate and heart rate variability were measured using a portable telemetry. Lameness was scored by three blinded boarded equine surgeons using the AAEP and 10-point scales. RESULTS: Mean maximum plasma concentration (Cmax ) for A20 was 20.01 µg/ml within 0.66 h (Tmax ) after administration; The mean Cmax for A30 was 30.02 µg/ml with a Tmax of 0.43 h. Post-treatment heart rate for A30 was significantly lower than A20 at 1 and 7 h; lower than PB at 2, 3, 4.5 and 7 h; lower than C at 2, 3.5, 4.5, 6, 7 and 8 h. 10-point Lameness scores were significantly improved for A30 than C at 2 and 4 h post-treatment; PB was significantly improved than C at 8 h post treatment. There were no significant differences in lameness between A20, A30 and PB. MAIN LIMITATIONS: Small sample size, lack of objective lameness measurement. CONCLUSIONS: Acetaminophen at 30 mg/kg produced a more rapid improvement in lameness scores and heart rate compared with other treatments in this model. Further evaluation of the pharmacokinetics and safety of repeated oral dosing of acetaminophen at 30 mg/kg is needed to determine clinical utility.

CONTEXTO: Acetaminofeno tem sido usado rotineiramente em cavalos com dor musculoesquelética, tanto como terapia solo quanto em associação com outros anti-inflamatórios não esteroides tradicionais. OBJETIVOS: Determinar a farmacocinética e eficácia de duas doses de acetaminofeno em cavalos com claudicação mecanicamente induzida, e comparar com fenilbutazona e placebo. DELINEAMENTO DO ESTUDO: Estudo randomizado, cego e controlado utilizando quadrado latino. METODOLOGIA: Nove éguas adultas com claudicação induzida mecanicamente pelo método de aplicação de pressão na sola através de ferradura foram tratadas com acetaminofeno (20 mg/kg VO; A20), acetaminofeno (30 mg/kg VO; A30), fenilbutazona (2.2 mg/kg, VO; PB) e placebo oral (C) em um estudo quadrado latino de forma randômica. Concentração plasmática dos grupos A20 e A30 foram analisadas pelo método LC-MS/MS e análise farmacocinética não compartimentar. Frequência cardíaca e variação da frequência cardíaca foram mensuradas usando telemetria portátil. O grau de claudicação foi avaliado usando a escala de 10 pontos da AAEP por três cirurgiões especialistas (board-certified) que estavam cegos ao tratamento. RESULTADOS: A média máxima da concentração plasmática (Cmax ) do grupo A20 foi 20.01 µg/ml dentro de 0.66 h (Tmax ) da administração. A média Cmax do grupo A30 foi 30.02 µg/ml dentro da Tmax de 0.43 h. A frequência cardíaca do grupo A30 foi significativamente mais baixa do que a do grupo A20 nos momentos 1 e 7 h; mais baixa do que o grupo PB nos momentos 2, 3, 4.5 e 7 h; e mais baixa do que as do grupo C nos momentos 2, 3.5, 4.5, 6, 7 e 8 h. O grau de claudicação diminuiu significativamente no grupo A30 quando comparado com o grupo C nos momentos 2 e 4 h pós tratamento, e no grupo PB quando comparado com o grupo C no momento 8 h pós tratamento. Não houve diferença significativa em grau de claudicação quando os grupos A20, A30 e PB foram comparados. PRINCIPAIS LIMITAÇÕES: Número pequeno de animais, ausência de mensuração de claudicação objetiva. CONCLUSÕES: A dose de 30 mg/kg de acetaminofeno proporcionou uma superior melhora na escala de claudicação e frequência cardíaca quando comparada com os outros tratamentos avaliados neste estudo. Mais informações sobre a farmacocinética e efeitos da repetida dosagem de 30 mg/kg de acetaminofeno precisam ser avaliadas para determinar a sua aplicabilidade clínica.

Pharmacokinetics and anti-inflammatory effects of flunixin meglumine as a sole agent and in combination with phenylbutazone in exercised Thoroughbred horses.

BACKGROUND: Flunixin meglumine (FM) and phenylbutazone (PBZ) are potent anti-inflammatory agents and as such their potential to mask injuries that would otherwise keep a horse from training or racing is concerning. A common practice in racetrack medicine in the USA is to administer the two drugs within close proximity (24 hours apart) of each other, raising the concern of pharmacokinetic interactions and enhanced anti-inflammatory effects. OBJECTIVES: Describe the pharmacokinetics and effects of PBZ on the clearance of FM when administered in close proximity as well as effects on inflammatory mediators. STUDY DESIGN: Two-way randomised balanced crossover experiment. METHODS: Twelve Thoroughbred exercised horses received 500 mg FM IV alone or in combination with 2 g of IV PBZ 24 hours later. Blood and urine samples were collected prior to and for up to 120 hours post-drug administration. Whole blood samples were collected at various times and challenged with lipopolysaccharide or calcium ionophore to induce ex vivo synthesis of eicosanoids. Concentrations of FM, PBZ and eicosanoids were measured using LC-MS/MS and noncompartmental pharmacokinetic analysis performed on concentration data. RESULTS: Flunixin meglumine clearance was significantly increased when horses received PBZ 24 hours post-administration (P = .03). No other differences in pharmacokinetic parameters were noted between groups. Thromboxane B2 was significantly suppressed, relative to baseline for 96 hours post-FM administration. Subsequent administration of PBZ prolonged the suppression. Prostaglandin E2 was decreased for 24 hours following administration of FM with subsequent administration of PBZ prolonging the suppression until 120 hours. PGF2alpha concentrations were decreased for up to 168 hours post-FM administration. FM administration significantly decreased 15-HETE. MAIN LIMITATIONS: Small sample size and lack of a phenylbutazone-only treatment group. CONCLUSIONS: Administration of PBZ post-FM administration increased FM clearance. The anti-inflammatory effects of FM appear to be prolonged when PBZ is administered 24 hours post-administration.

Identification and characterization of the enzymes responsible for the metabolism of the non-steroidal anti-inflammatory drugs, flunixin meglumine and phenylbutazone, in horses.

The in vivo metabolism and pharmacokinetics of flunixin meglumine and phenylbutazone have been extensively characterized; however, there are no published reports describing the in vitro metabolism, specifically the enzymes responsible for the biotransformation of these compounds in horses. Due to their widespread use and, therefore, increased potential for drug-drug interactions and widespread differences in drug disposition, this study aims to build on the limited current knowledge regarding P450-mediated metabolism in horses. Drugs were incubated with equine liver microsomes and a panel of recombinant equine P450s. Incubation of phenylbutazone in microsomes generated oxyphenbutazone and gamma-hydroxy phenylbutazone. Microsomal incubations with flunixin meglumine generated 5-OH flunixin, with a kinetic profile suggestive of substrate inhibition. In recombinant P450 assays, equine CYP3A97 was the only enzyme capable of generating oxyphenbutazone while several members of the equine CYP3A family and CYP1A1 were capable of catalyzing the biotransformation of flunixin to 5-OH flunixin. Flunixin meglumine metabolism by CYP1A1 and CYP3A93 showed a profile characteristic of biphasic kinetics, suggesting two substrate binding sites. The current study identifies specific enzymes responsible for the metabolism of two NSAIDs in horses and provides the basis for future study of drug-drug interactions and identification of reasons for varying pharmacokinetics between horses.

Analysis of phenylbutazone residues in horse tissues with and without enzyme-hydrolysis by LC-MS/MS.

Phenylbutazone (PBZ) is permitted to be used for the treatment of musculoskeletal pain and inflammation in race horses but it is not approved for use in horses destined for human consumption. In a recent study initiated in our laboratory to study the disposition of PBZ and its oxyphenbutazone (OXPBZ) metabolite in equine tissues, we compared the effect of an additional enzymatic hydrolysis step with ß-glucuronidase on the results of the analysis for PBZ without enzymatic hydrolysis. Incurred tissue samples obtained from a female horse dosed with PBZ at 8.8 mg/kg for 3 days and sacrificed 6 days following the last administration were used for this study. Liver, kidney, and muscle tissues were collected, extracted, cleaned up on a silica-based solid-phase extraction (SPE) preceded by a weak-anion exchange SPE and analyzed with our in-house validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for PBZ and OXPBZ. Addition of the hydrolysis step resulted in a significant increase in recovery of both PBZ and OXPBZ residues. © 2016 Her Majesty the Queen in Right of Canada. Drug Testing and Analysis © 2016 John Wiley & Sons, Ltd.

Pharmacokinetics of methocarbamol and phenylbutazone in exercised Thoroughbred horses.

Methocarbamol (MCBL) is commonly used in performance horses for the treatment of skeletal muscle disorders. Current regulatory recommendations for show horses and racehorses are based on a single oral dose of 5 g, although doses in excess of this are often administered. The goal of the current study was to characterize the disposition of MCBL following higher dose administration and administration in combination with another commonly used drug in performance horses, phenylbutazone (PBZ). Exercised Thoroughbred horses were administered various doses of MCBL as a sole agent and MCBL in combination with PBZ. Blood samples were collected at various times, concentrations of MCBL and PBZ measured using LC-MS/MS and pharmacokinetic parameters calculated using compartmental analysis. Following administration of 15 g of MCBL, either as part of a single- or multiple-dose regimen, a number of horses exceeded the Association of Racing Commissioners International and the United States Equestrian Federation's recommended regulatory threshold at the recommended withdrawal time. There was not a significant difference between horses that received only MCBL and those that received MCBL and PBZ. Results of the current study support an extended withdrawal guideline when doses in excess of 5 g are administered.

Phenylbutazone, a New Long-Acting Agent that can Improve the Peptide Pharmacokinetic Based on Serum Albumin as a Drug Carrier.

As a NPY-2 receptor agonist, PYY24-36- Leu31 is reported to suppress appetite and has a potential in obesity treatment, but its short half-life limits the clinical application. The use of chemical modification to improve interactions with human serum albumin (HSA) is an effective strategy for prolonging the half-lives of peptide analogues. So based on the characteristics that phenylbutazone has a good combination with HSA, we selected a proper linker to link with PYY24-36 -Leu31 to create long-acting and highly biologically active PYY24-36 -Leu31 conjugates, and successfully find a novel, long-acting PYY24-36 -Leu31 conjugate 8 that, when dosed every other day in diet induce obese (DIO) mice for 2 weeks, results in a significant reduction in food intake and body weight and improvement in blood parameter and hepatic steatosis.

The Safety and Pharmacokinetics of Carprofen, Flunixin and Phenylbutazone in the Cape Vulture (Gyps coprotheres) following Oral Exposure.

The following study evaluates the overt toxic potential of carprofen (CRP), flunixin (FXN) and phenylbutazone (PBZ) in Old world vultures in relation to historic toxicity data for diclofenac and ketoprofen, with the Cape vulture (Gyps coprotheres) being the indicator species. The toxic potential of a single oral dose of CRP (11.5 mg/kg), FXN (1 mg/kg),PBZ (1.7 mg/kg) or water was evaluated by means of a four-way parallel study (n = 2), as means of ascertaining if these drugs were as toxic as diclofenac in the vulture. No unscheduled deaths or pathological lesions were noted following exposure. Clinical signs of lethargy and depression were, however, noted in one CRP, two FXN and one PBZ treated birds. Mild reversible inhibition of UA excretion was evident in all three groups, although UA remained within the population reference interval in contrast to the effects previously described for diclofenac and ketoprofen. All treatment groups had a drug concentration responsive increase in alanine transferase activity. CRP, FXN and PBZ were characterised by a maximum plasma concentration (Cmax) of 1051.8 ± 620.7 ng/ml, 335.9 ± 36.3 ng/ml and 11150 ± 2474.9 ng/ml at 4 ± 4.3, 0.45 ± 0.02 and 5.3 ± 5.2 hours (Tmax) respectively and a half-life of elimination of 13.3 ±5, 1.8±1 and 18.7 ±11.4 hours respectively. While we could not demonstrate a lethal effect of the tested substances, the presence of toxic clinical signs, clinical pathological changes and/or long half-lives of elimination suggests that all three drugs have a potential for toxicity in a larger population or on repeat administration. In conclusion while the studied substances were not as overtly toxic as diclofenac, they are of safety concern.

Multiresidue determination of ten nonsteroidal anti-inflammatory drugs in bovine, porcine, and chicken liver tissues by HPLC-MS/MS.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the group of drugs having the therapeutic efficacy of analgesic and antipyretic. To detect health-threatening residues of NSAIDs, a fast and easy multiresidue method based on liquid chromatography tandem mass spectrometry (LC-MS/MS) was described. Ten NSAIDs were extracted from the tissues using 2 mL of acetonitrile and 0.1 mL of 2 mM ammonium formate in distilled water. After clean-up using C18 sorbent, it was evaporated under nitrogen, reconstituted with 1 mL distilled water and analyzed by LC-MS/MS. The method was validated based on guideline for residue testing laboratory. Furthermore, the method has also been applied successfully to detect ten NSAIDs from bovine, porcine, and chicken liver tissues. In a total of 315 liver samples tested, acetylic salicylic acid was detected from 28 porcine and 2 chicken liver tissues at levels of 13 ∼ 576 and 50 ∼ 53 ng/g, respectively. Subsequently, paracetamol was detected in 15 porcine liver tissues with a detection levels of 28 ∼ 381 ng/g. Phenylbutazone and its metabolite, oxyphenylbutazone, were detected at 247 and 15 ng/g range in one of the bovine liver tissue, respectively.

Is phenylbutazone a genotoxic carcinogen? A weight-of-evidence assessment.

Published in silico, in vitro, in vivo laboratory animal and human data, together with information on biotransformation and data from structure-activity analyses with two decision-tree systems (ACToR and Toxtree), have been used in a weight-of-evidence (WoE) assessment to determine whether phenylbutazone (PBZ) is a genotoxic or a non-genotoxic carcinogen. This was undertaken to facilitate the risk assessment of human exposure to this veterinary drug via the consumption of horsemeat from treated animals. Despite problems with data interpretation at all tiers of the database, it was concluded that PBZ behaves like a genotoxic carcinogen with a threshold dose. This conclusion is based mainly on the results of a definitive rodent bioassay, and on the following observations: a) that PBZ has weak in vitro activity only at high concentrations in some genotoxicity assays, accompanied by high levels of cytotoxicity; b) that it (and a major metabolite) is able to cause sister chromatid exchanges in vivo in rodents; and c) that it can induce cytogenetic effects in vivo in humans. It also takes into account the known and predicted activities of the parent drug, some of its metabolites and two structural analogues, and, importantly, several of the drug's other biochemical effects that are unrelated to toxicity. However, this conclusion is not fully supported by all the evidence, and much of the information is based on old papers. Therefore, more studies are required to establish whether the concentration thresholds seen in vitro would translate to dose thresholds for carcinogenicity, such that a safe dose-level could be defined for the purposes of assessing risk. It was disappointing that a WoE approach to evaluating all of the available hazard data, as is increasingly being advocated to improve the hazard identification paradigm, was unable to provide definitive answers in this case, particularly in view of the large numbers of animals that had been used to provide much of the information.

Pharmacokinetics, pharmacodynamics, metabolism, toxicology and residues of phenylbutazone in humans and horses.

The presence of horse meat in food products destined for human consumption and labelled as beef has raised several concerns of public interest. This review deals solely with one aspect of these concerns; samples of equine tissue from horses destined for the human food chain have tested positive for the non-steroidal anti-inflammatory drug, phenylbutazone. The safety of some or all such foods for human consumers is a major concern, because it was shown many years ago that phenylbutazone therapy in humans can be associated with life threatening blood dyscrasias. As an initial basis for assessing the potential toxicity of foods containing phenylbutazone and its metabolites, this article reviews (1) the pharmacokinetic, pharmacodynamic, metabolic and toxicological profiles of phenylbutazone, with particular reference to horses and humans; (2) toxicity data in laboratory animals; (3) phenylbutazone residues in food producing species, and (4) as a preliminary assessment, the potential hazard associated with the consumption of horse meat containing phenylbutazone and its metabolites. Since phenylbutazone cannot be classified as a carcinogenic substance in humans, and noting that blood dyscrasias in humans are likely to be dose and treatment duration-dependent, the illegal and erratic presence of trace amount residues of phenylbutazone in horse meat is not a public health issue.

Phenylbutazone and flunixin meglumine used singly or in combination in experimental lameness in horses.

REASON FOR PERFORMING STUDY: Using an adjustable heart bar shoe model of foot pain, the objective of this study was to test the hypothesis that the combined use of phenylbutazone (PBZ) and flunixin meglumine (FM) would prove more efficacious in alleviating lameness than either drug alone. MATERIALS AND METHODS: One hour after induction of lameness at weekly intervals, 8 healthy adult Thoroughbred horses randomly underwent one of 4 i.v. treatments: saline (SAL) placebo (1 ml/45 kg bwt), PBZ (4.4 mg/kg bwt), FM (1.1 mg/kg bwt) or PBZ+FM (at the same dosages as given individually). Heart rate (HR) and lameness score (LS) responses were assessed in a blinded manner every 20 min for 5 h after lameness induction and then hourly for 12 h after treatment. Jugular venous blood samples were obtained at -1, 0, 0.05, 1, 2, 4, 6, 8, 10 and 12 h and subsequently analysed for drug concentrations. Repeated measures ANOVA and post hoc Tukey's test were used to identify analgesic effects at a significance level of P<0.05. RESULTS: Heart rate was lower in all nonsteroidal anti-inflammatory drug (NSAID)-treated trials from 2 h to 10 h post treatment (P<0.05). Analgesic effects of FM and PBZ+FM, as evidenced by decreases in HR, lasted for 12 h post treatment (P<0.05). Lameness score decreased earlier in PBZ and PBZ+FM trials than in FM trials (P<0.05) and the analgesic effect on LS lasted for 12 h post treatment for all NSAID trials (P<0.05). Peak PBZ plasma concentration was 73.7 ± 6.0 and 77.9 ± 5.5 µg/ml. Peak FM concentration was 12.0 ± 0.8 and 13.7 ± 1.0 µg/ml. CONCLUSIONS: It was concluded that the combination of PBZ+FM was not more effective than either PBZ or FM alone. These data do not support the hypothesis that the combination is more efficacious at these dosages than either drug alone in this model of acute foot pain.

Competitive binding to plasma thyroid hormone transport proteins and thyroid disruption by phenylbutazone used as a probe.

A model of thyroidectomized sheep intravenously supplemented with thyroid hormone (TH) was developed to mimic endogenous TH exposure and to analyze the impact on plasma TH homeostasis of xenobiotic interference with TH binding to plasma proteins. TH was displaced from plasma protein binding sites by using phenylbutazone (PBZ) as a test xenobiotic, to compare the effect of PBZ on steady state free and total plasma TH concentrations between the in vivo situation and an in vitro system. While PBZ increased free TH in vitro, PBZ administration in vivo produced an immediate reduction in both total and free plasma TH. The decrease in the total TH was consistent with a PBZ-induced displacement of TH from its plasma binding proteins, leading to an increase in total TH plasma clearance. However, this reduction in total TH was not expected to be accompanied by a parallel decrease in free plasma TH since the free TH is determined by the clearance of the free plasma TH. This suggested that PBZ may also have interfered with the clearance mechanisms of free TH. It can be concluded that our thyroidectomized sheep model enables a dual action of a xenobiotic on plasma TH to be distinguished, namely a displacement of TH from its binding proteins leading to a decrease in the total plasma concentration, which is not relevant to thyroid function versus an interference with the intrinsic TH clearance leading to a change in the free plasma TH, which has a major impact in terms of thyroid disruption.

Comparison of generation 3 polyamidoamine dendrimer and generation 4 polypropylenimine dendrimer on drug loading, complex structure, release behavior, and cytotoxicity.

BACKGROUND: Polyamidoamine (PAMAM) and polypropylenimine (PPI) dendrimers are the commercially available and most widely used dendrimers in pharmaceutical sciences and biomedical engineering. In the present study, the loading and release behaviors of generation 3 PAMAM and generation 4 PPI dendrimers with the same amount of surface amine groups (32 per dendrimer) were compared using phenylbutazone as a model drug. METHODS: The dendrimer-phenylbutazone complexes were characterized by (1)H nuclear magnetic resonance and nuclear Overhauser effect techniques, and the cytotoxicity of each dendrimer was evaluated. RESULTS: Aqueous solubility results suggest that the generation 3 PAMAM dendrimer has a much higher loading ability towards phenylbutazone in comparison with the generation 4 PPI dendrimer at high phenylbutazone-dendrimer feeding ratios. Drug release was much slower from the generation 3 PAMAM matrix than from the generation 4 PPI dendrimer. In addition, the generation 3 PAMAM dendrimer is at least 50-fold less toxic than generation 4 PPI dendrimer on MCF-7 and A549 cell lines. CONCLUSION: Although the nuclear Overhauser effect nuclear magnetic resonance results reveal that the generation 4 PPI dendrimer with a more hydrophobic interior encapsulates more phenylbutazone, the PPI dendrimer-phenylbutazone inclusion is not stable in aqueous solution, which poses a great challenge during drug development.

Effect of an endurance-like exercise on the disposition and detection time of phenylbutazone and dexamethasone in the horse: application to medication control.

REASONS FOR PERFORMING STUDY: Equine antidoping rules were established to prevent a horse's performance being altered after the administration of prohibited substances, including approved drugs used for legitimate treatment. Veterinarians have to advise owners or trainers on appropriate withholding times to guarantee that their horses may safely compete after drug administration. In order to propose tailored withdrawal times, several horse organisations released detection time (DT) values, for the main veterinary drugs used in horses. One of the possible limits to the information provided by published DTs in horses is the fact that they are determined from classic pharmacokinetic studies performed at rest under laboratory conditions. In field conditions, training and exercise programmes may have an influence on drug elimination. METHODS: Dexamethasone (DMX) and phenylbutazone (PBZ) have been quantified in plasma and urine after solid phase extraction. The kinetic disposition of DXM (8 microg/kg) and PBZ (8 mg/kg) administered by i.v. route in 8 horses, was investigated in rest conditions and during a standardised 3 h test exercise according to a cross-over design. OBJECTIVES: The aim of the present study was to compare the kinetic disposition of 2 test drugs, DMX and PBZ in rest vs. exercising conditions. RESULTS: It was shown in 8 horses that a sustained 3 h of mild exercise slightly decreased the plasma clearance of both drugs (about 25% for DXM and 37% for PBZ) and this is mainly explained by the significant decrease of the corresponding hepatic clearance. In addition, as the volume of distribution was correlatively decreased, the plasma terminal half-life, which is a hybrid parameter of plasma clearance and volume of distribution, remains unchanged overall. CONCLUSION AND POTENTIAL RELEVANCE: Establishing DTs or withdrawal times (WTs) are relevant as plasma and urine half-lives, but not clearance, are the main determinants of DT length. Veterinarians may realistically decide upon a WT for a legitimate drug based on the corresponding DT obtained under resting conditions providing this drug has a low hepatic extraction ratio and a safety margin is added to allow for all possible sources of variability.

Pharmacokinetics of orally administered phenylbutazone in African and Asian elephants (Loxodonta africana and Elephas maximus).

The pharmacokinetic parameters of phenylbutazone were determined in 18 elephants (Loxodonta africana and Elephas maximus) after single-dose oral administration of 2, 3, and 4 mg/kg phenylbutazone, as well as multiple-dose administrations with a 4-wk washout period between trials. After administration of 2 mg/kg phenylbutazone, mean serum concentrations peaked in approximately 7.5 hr at 4.3 +/- 2.02 microg/ml and 9.7 hr at 7.1 +/- 2.36 microg/ml for African and Asian elephants, respectively, while 3 mg/kg dosages resulted in peak serum concentrations of 7.2 +/- 4.06 microg/ml in 8.4 hr and 12.1 +/- 3.13 microg/ml in 14 hr. The harmonic mean half-life was long, ranging between 13 and 15 hr and 39 and 45 hr for African and Asian elephants, respectively. There was evidence of enterohepatic cycling of phenylbutazone in Asian elephants. Significant differences (P < 0.0001) in pharmacokinetic values occurred between African and Asian elephants for clearance (27.9 and 7.6 ml/hr/kg, respectively), terminal half-life (15.0 and 38.7 hr, respectively), and mean residence time (22.5 and 55.5 hr, respectively) using 2-mg/kg dosages as an example. This suggests that different treatment regimens for Asian and African elephants should be used. There were no apparent gender differences in these parameters for either elephant species.

Simultaneous and minimally invasive assessment of muscle tolerance and bioavailability of different volumes of an intramuscular formulation in the same animals.

Evaluation of skeletal muscle tolerance during development of new drug formulations for i.m. use is most often based on terminal methods performed in the target species after slaughtering. The objective of this study was to evaluate the effect of muscle damage on the pharmacokinetic parameters of the drug delivered into the muscle using an alternative, noninvasive method. Phenylbutazone (PBZ) was used as the test article. Six ewes received increasing volumes of a 20% PBZ i.m. formulation, according to a cross-over design, and an i.v. bolus of the same formulation. Serial blood samples were taken, and a pharmacokinetic analysis of the plasma activity of creatine kinase and plasma PBZ concentrations was carried out. The amount of muscle damage after i.m. administration of 2, 4, or 8 mL of PBZ, calculated from the area under the curve of plasma creatine kinase across time was 36, 76, and 178 g for a 70-kg ewe. The corresponding absolute bioavailability of PBZ was 100 +/- 32%, 96 +/- 19%, and 100 +/- 17%, and the maximal PBZ concentrations were 42 +/- 3.4, 74 +/- 8.8, and 119 +/- 18.2 microg/mL. The plasma clearance of PBZ (i.v.) was 4.2 +/- 0.94 mL.kg(-1).h(-1). In conclusion, the absolute bioavailability of PBZ after i.m. administration was not altered by the increased volume of formulation administered despite the overall increase in the extent of muscle damage.

Comparison of the effect of Sporobolus virginicus and Rhodes (Chloris gayana) hay diets on the absorption pattern of phenylbutazone in the camel (Camelus dromedarius).

The effect of feeding Sporobolus and Rhodes hay on phenylbutazone (4 g) relative absorption was examined in six camels using a two-period, two-sequence, two-treatment crossover design. Serum concentration of the drug was measured by high performance liquid chromatography. The measured values (means+/-SD) for Rhodes and Sporobolus hay, respectively, were Cmax 35.59+/-22.36 and 36.55+/-18.99 microg/mL, Tmax 26+/-2.53 and 26.3+/-1.97 h and AUC0-72 h 1552+/-872.6 and 1621+/-903.6 microg h/mL. Broad plateau concentrations of phenylbutazone in serum were observed between 12 and 36 h. There was no significant difference in any parameter between the two feeding regimens. Multiple peaks in serum concentration-time curve were observed, regardless of the type of grass available to and the animals prior to drug administration. It was concluded that the phasic absorption of phenylbutazone was a particular feature of hay feeding in camels, and the Sporobolus hay can be fed to camels without any effect on the rate and extent of phenylbutazone absorption compared to Rhodes grass hay.