PHARMACOKINETICS OF ORAL FLUNIXIN MEGLUMINE, MELOXICAM, OR GABAPENTIN IN THREE BLACK RHINOCEROS (DICEROS BICORNIS).

Pharmacokinetics of single, separate doses of IV flunixin meglumine (1 mg/kg), IV meloxicam (0.5 mg/kg), oral flunixin meglumine (1 mg/kg), oral meloxicam (1 mg/kg), and oral gabapentin (15 mg/kg) in three adult black rhinoceroses (Diceros bicornis) were determined from serial blood collection made over 72 h. The concentration versus time profiles were analyzed for each drug and route in each individual rhinoceros, and individual pharmacokinetic parameters were calculated for each medication administered. Meloxicam had near complete bioavailability in each trial, while flunixin meglumine was generally lower. Oral meloxicam was noted with similar half-life values between all animals (range 9.22-14.52 h) tested, while oral gabapentin had a larger range (range 10.25-24.85 h). Oral flunixin meglumine achieved a lower Cmax (range 170.67-664.38 ng/ml) in this study compared with the mean Cmax (1,207 ng/ml) reported in a similar study in white rhinoceroses (Ceratotherium simum), but some overlap in range of values was noted. Oral flunixin meglumine Tmax (range 1.05-10.78 h) and half-life (range 3.88-14.85 h) values in black rhinoceroses was similar to mean values reported in white rhinoceroses (3 and 8.3 h, respectively).

Pharmacokinetics, Milk Residues, and Toxicological Evaluation of a Single High Dose of Meloxicam Administered at 30 mg/kg per os to Lactating Dairy Cattle.

Adverse effects associated with overdose of NSAIDs are rarely reported in cattle, and the risk level is unknown. If high doses of NSAIDs can be safely administered to cattle, this may provide a longer duration of analgesia than using current doses where repeated administration is not practical. Meloxicam was administered to 5 mid-lactation Holstein dairy cows orally at 30 mg/kg, which is 30 times higher than the recommended 1 mg/kg oral dose. Plasma and milk meloxicam concentrations were determined using high-pressure liquid chromatography with mass spectroscopy (HPLC-MS). Pharmacokinetic analysis was performed by using noncompartmental analysis. The geometric mean maximum plasma concentration (Cmax) was 91.06 µg/mL at 19.71 h (Tmax), and the terminal elimination half-life (T1/2) was 13.79 h. The geometric mean maximum milk concentration was 33.43 µg/mL at 23.74 h, with a terminal elimination half-life of 12.23 h. A thorough investigation into the potential adverse effects of a meloxicam overdose was performed, with no significant abnormalities reported. The cows were humanely euthanized at 10 d after the treatment, and no gross or histologic lesions were identified. As expected, significantly higher plasma and milk concentrations were attained after the administration of 30 mg/kg meloxicam with similar half-lives to previously published reports. However, no identifiable adverse effects were observed with a drug dose 30 times greater than the industry uses within 10 days of treatment. More research is needed to determine the tissue withdrawal period, safety, and efficacy of meloxicam after a dose of this magnitude in dairy cattle.

Corrigendum: Comparative Pharmacokinetics of Meloxicam Between Healthy Post-partum vs. Mid-lactation Dairy Cattle.

[This corrects the article DOI: 10.3389/fvets.2020.00548.].

Pharmacokinetics and Tissue Levels of Pantoprazole in Neonatal Calves After Intravenous Administration.

Background: Neonatal calves are at risk of developing abomasal ulceration, but there is a lack of pharmacokinetic data for potential anti-ulcerative therapies, such as pantoprazole, in ruminant species. Objective: The study objectives were to estimate plasma pharmacokinetic parameters for pantoprazole in neonatal dairy calves after intravenous (IV) administration. A secondary objective was to quantify the concentrations of pantoprazole in edible tissues after IV dosing. Methods: Pantoprazole was administered to 9 neonatal Holstein calves at a dose of 1 mg/kg IV. Plasma samples were collected over 24 h and analyzed via HPLC-MS for determining pantoprazole concentrations. Pharmacokinetic parameters were derived via non-compartmental analysis. Tissue samples were collected at 1, 3, and 5 days after administration and analyzed via HPLC-MS. Results: Following IV administration, plasma clearance, elimination half-life, and volume of distribution of pantoprazole were estimated at 4.46 mL/kg/min, 2.81 h, and 0.301 L/kg, respectively. The global extraction ratio was estimated at 0.053 ± 0.015. No pantoprazole was detected in the edible tissues 1, 3, or 5 days after administration. A metabolite, pantoprazole sulfone was detected in all the edible tissues 1 and 3 days after administration. Conclusion: The reported plasma clearance for pantoprazole is less than that reported for alpacas but higher than reported in foals. The elimination half-life in calves appears to be longer than observed in foals and alpacas. While pantoprazole sulfone was detected in the tissues after IV administration, further research is needed as to the metabolism and potential tissue accumulation of other pantoprazole metabolites in calves. Future pharmacodynamic studies are necessary to determine the efficacy of pantoprazole on abomasal acid suppression in calves.

Tear Film Pharmacokinetics and Systemic Absorption Following Topical Administration of 1% Prednisolone Acetate Ophthalmic Suspension in Dogs.

The study aimed to determine the tear film pharmacokinetics following topical administration of 1% prednisolone acetate-assessing whether two drops would provide a superior kinetic profile compared to one drop-and to determine the fraction of an eye drop that reaches the systemic circulation in dogs. Two separate experiments were conducted in eight healthy Beagle dogs: (i) Instillation of 1 drop (35 µL) or 2 drops (70 µL) of 1% prednisolone acetate ophthalmic suspension in each eye, followed by tear collections with Schirmer strips from 0 to 720 min; (ii) Instillation of 1 or 2 drops of 1% prednisolone acetate in both eyes 4 times daily for 3 days, followed by blood collection 10-15 min after each topical administration on Day 3. Tear and blood samples were analyzed with high performance liquid chromatography to determine the levels of prodrug (prednisolone acetate), active metabolite (prednisolone) and total prednisolone (prednisolonetotal = prodrug + active metabolite). Prednisolone levels represented 10 and 72% of prednisolonetotal concentrations in tears and plasma, respectively, indicating a greater hydrolysis of prodrug in the blood vs. tear compartment. For eyes receiving one or two drops, tear film prednisolonetotal concentrations were high (~3.1 mg/mL) immediately following topical administration but rapidly decreased by ~45% at 1 min and ~95% at 15 min. No differences were noted between 1 vs. 2 drops in tear film prednisolonetotal concentrations (including maximal concentration, Cmax) or residual drug levels in tears at any time point (P ≥ 0.097); however, instillation of 2 drops provided a higher average tear concentration (Cavg) and overall drug exposure to the ocular surface (AUClast) over the 12-h sampling period (P = 0.009). Average plasma prednisolonetotal concentration represented ≤ 2% of the dose applied to the ocular surface, and did not differ significantly for dogs receiving 1 drop (17 ng/mL) or 2 drops (20 ng/mL) 4 times daily for 3 days (P = 0.438). In sum, topical corticotherapy is beneficial for inflammatory conditions of the canine anterior segment given the relatively high concentrations achieved in tears, although caution is warranted to prevent unwanted local or systemic adverse effects.

Comparative Pharmacokinetics of Meloxicam Between Healthy Post-partum vs. Mid-lactation Dairy Cattle.

Lactating dairy cattle are at risk for various painful conditions throughout their life, such as lameness, parturition, mastitis, and metabolic disorders. These conditions necessitate adequate methods of analgesia to address welfare concerns through efficacious pain mitigation. As no method of analgesia has been approved for lactating dairy cattle, to date, research is necessary to determine effective pain management strategies for dairy cattle. In both the European Union and Canada, meloxicam has been approved for use in lactating dairy cattle as a methodology for pain control. The objective of this study was to characterize the pharmacokinetics of meloxicam administered orally and intravenously to lactating dairy cattle in the post-partum vs. mid-lactation period. In this parallel study design, 12 healthy, lactating Holsteins were enrolled within 24 h of freshening and randomly allocated to intravenous (0.2 mg/kg) or oral (1.0 mg/kg) meloxicam administration treatment groups. They were matched based on parity to 12, healthy cows that were considered mid-lactation [>150 days-in-milk (DIM)] to receive the same treatment. Based on meloxicam formulation, sampling times varied and plasma was collection via jugular venipuncture for 6 days. Plasma drug concentrations were evaluated using liquid chromatography coupled with mass spectroscopy and pharmacokinetic properties were evaluated using non-compartmental (i.e., statistical moments) analysis. Results indicated a decreased systemic clearance of meloxicam in post-partum relative to mid-lactation cows, which resulted in a longer half-life and increased total exposure independent of mode of administration. These results suggest a need for dose adjustments based on stage in lactation and further assessment of the impact of days-in-milk on milk withholding period.

Pharmacokinetics and tissue concentrations of firocoxib in sows following oral administration.

The objectives of this study were to describe the pharmacokinetics of firocoxib following oral (PO) dosing and intravenous (IV) injection in sows. Seven healthy sows were administered 0.5 mg firocoxib/kg IV. Following a 23-d washout period, sows were administered firocoxib at 4.0 mg firocoxib/kg PO. Blood samples were collected at predetermined times for 72 hr after IV and 120 hr after PO administration. Plasma firocoxib concentration was measured using UPLC-MS/MS, and pharmacokinetic analysis was performed using noncompartmental procedures. Tissue firocoxib concentrations were determined at 5, 10 (n = 2/time point), and 21 d (n = 3) after PO administration. The geometric mean half-life following IV and PO administration was 16.6 and 22.5 hr, respectively. A mean peak plasma concentration (Cmax) of 0.06 µg/ml was recorded at 7.41 hr (Tmax ) after oral administration. Mean oral bioavailability was determined to be 70.3%. No signs of NSAID toxicity were observed on macroscopic and microscopic investigation. Firocoxib was detected in the skin with subcutaneous fat (0.02 µg/g) of one of three sows at 21 days postadministration. Additional work to establish appropriate meat withhold intervals in sows is required. Firocoxib was readily absorbed following PO administration. Further work is needed to better understand the analgesic effects for sows and piglets nursing sows administered firocoxib.

Tissue residue depletion and estimation of extralabel meat withdrawal intervals for tulathromycin in calves after pneumatic dart administration.

The objectives of this study were to evaluate the injection site pathology and determine tissue residue depletion of tulathromycin in calves following pneumatic dart administration and to calculate the associated extralabel withdrawal interval (WDI). Castrated male Holstein calves were injected with ~2.6 mg/kg tulathromycin via pneumatic dart administration. At 1 (n = 2), 6, 12, 18, and 24 d after drug injection (n = 3/time point), calves were euthanized, and muscle, liver, kidney, fat, and injection site samples were harvested and analyzed for tulathromycin concentrations using a LC-MS/MS method. Gross pathology and histopathology evaluations on the injection site samples were also performed. Pneumatic dart administration of tulathromycin caused severe localized lesions of hemorrhage and edema on days 1 and 6, as well as severe pathological reactions in the subcutaneous muscle on days 1, 6, and 12. Slight to moderate reactions were still observed in the majority of the skin or subcutaneous/muscle samples on day 24. Measured tulathromycin concentrations were converted to calculate the concentrations of the marker residue CP-60,300 by dividing a conversion factor of 1.4. The data were used to calculate extralabel WDIs based on the guidelines from U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The results showed that tulathromycin concentrations were the highest in the liver (4,877.84 ± 65.33 µg/kg), kidney (5,819.52 ± 1,087.00 µg/kg), muscle (1,717.04 ± 140.35 µg/kg), injection site (51,884.05 ± 7,529.34 µg/kg), and fat (161.69 ± 36.48 µg/kg) at 6, 1, 1, 1, and 1 d, respectively, after treatment. Tulathromycin concentrations remained above the limit of quantification of 5 µg/kg in all tissues at 24 d. The calculated WDIs based on kidney data were 26 d using EMA method, 36 d using FDA method based on CP-60,300 data, and 45 d using FDA method based on tulathromycin data. These results suggest that pneumatic dart administration of tulathromycin causes injection site reactions in calves and an extended WDI is needed. One limitation of this study was the small sample size of 3 that did not meet FDA guideline requirement. Therefore, the calculated WDIs should be considered as preliminary and additional studies that use a larger number of animals and directly measure the concentrations of the marker residue CP-60,300 are needed to make a more conclusive recommendation on the extralabel WDI.

Tear Fluid Pharmacokinetics Following Oral Prednisone Administration in Dogs With and Without Conjunctivitis.

Purpose: To describe the pharmacokinetics (PK) of prednisone and prednisolone in tear fluid of dogs receiving oral prednisone at anti-inflammatory to immunosuppressive doses and to assess the impact of induced conjunctivitis on lacrimal drug levels. Methods: Six healthy Beagle dogs were administered 4 courses of prednisone at 0.5, 1.0, 2.0, and 4.0 mg/kg given orally once a day for 5 days. At steady state, topical histamine was applied to induce mild (1 mg/mL) or severe (375 mg/mL) conjunctivitis in 1 eye of each dog and tear samples were collected from both eyes at selected times. Prednisone and prednisolone were quantified in tears by liquid chromatography-mass spectrometry. Results: Lacrimal prednisone and prednisolone concentrations ranged from 2 to 523 ng/mL and 5 to 191 ng/mL, respectively. Drug concentrations were overall greater in dogs receiving higher doses of prednisone, but were not correlated with tear flow rate. Eyes with conjunctivitis often had larger amounts of prednisone and prednisolone in tear fluid compared to control eyes (up to +64%), but differences were not statistically significant. Significantly greater, but clinically insignificant, levels of prednisolone were found in eyes with severe versus mild conjunctivitis for oral prednisone doses ≥1.0 mg/kg. Conclusions: Disruption of the blood-tear barrier with conjunctivitis did not significantly affect drug levels in tears. Based on drug PK in tears, oral prednisone is likely safe for the management of reflex uveitis and ocular surface diseases. However, further prospective trials using systemic corticotherapy in diseased animals are warranted to confirm findings from this preclinical study.

Transmammary delivery of firocoxib to piglets reduces stress and improves average daily gain after castration, tail docking, and teeth clipping1.

Painful processing procedures in piglets such as tail docking, castration, and teeth clipping are an emerging animal welfare concern. We hypothesized that transmammary delivery of a nonsteroidal anti-inflammatory drug, firocoxib, would reduce pain associated with processing in piglets. This study compared the pharmacokinetics, efficacy, safety, and tissue residue concentrations of 4 doses of firocoxib (0.5, 1.0, 1.5, or 2.0 mg/kg) administered to sows and delivered to nursing piglets prior to processing. Sixteen sows, 5 ± 2 d postpartum, were randomly assigned to 1 of 4 treatment groups. On day 0, sows received a single intramuscular dose of firocoxib at 7 ± 1 h before piglet surgical castration, tail docking, and teeth clipping (males) or sham handling (females). Firocoxib and cortisol concentrations were determined from selected samples collected from sows and 3 piglets per litter (2 barrows and 1 gilt) at 0, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h after drug administration. On day 21, piglets were weighed and all animals were euthanized and necropsied. Tissues were collected from 3 piglets per litter for histological examination and drug residue analysis. Mean (±SEM) peak plasma firocoxib concentrations (Cmax) were 107.90 ± 15.18, 157.50 ± 24.91, 343.68 ± 78.89, and 452.83 ± 90.27 ng/mL in sows receiving 0.5, 1.0, 1.5, and 2.0 mg/kg firocoxib, respectively, and 9.53 ± 1.21, 31.04 ± 6.79, 53.30 ± 11.1, and 44.03 ± 7.47 ng/mL in their respective piglets. Mean plasma terminal half-life values ranged from 26 to 31 h in sows and 30 to 48 h in piglets. Barrows nursing sows that received 2.0 mg/kg firocoxib had a lower mean plasma cortisol concentration at 1 ± 1 h after processing compared with barrows nursing sows that received 1.0 mg/kg (P = 0.0416) and 0.5 mg/kg of firocoxib (P = 0.0397). From processing to weaning, litters of sows receiving 2.0 mg/kg firocoxib gained more weight than litters of sows that received 0.5 mg/kg (P = 0.008) or 1.0 mg/kg (P = 0.005). No signs of nonsteroidal anti-inflammatory drug toxicity were observed on examination of the kidney, liver, stomach, and small intestine, and concentrations of firocoxib and the descyclopropylmethyl metabolite were below the limit of detection (0.01 µg/g) in all tissues examined from sows and piglets. These findings indicate that maternal delivery of firocoxib to suckling piglets before tail docking and castration may safely reduce processing-induced stress and enhance production by increasing weaning weights.

An integrated experimental and physiologically based pharmacokinetic modeling study of penicillin G in heavy sows.

Penicillin G is widely used in food-producing animals at extralabel doses and is one of the most frequently identified violative drug residues in animal-derived food products. In this study, the plasma pharmacokinetics and tissue residue depletion of penicillin G in heavy sows after repeated intramuscular administrations at label (6.5 mg/kg) and 5 × label (32.5 mg/kg) doses were determined. Plasma, urine, and environmental samples were tested as potential antemortem markers for penicillin G residues. The collected new data and other available data from the literature were used to develop a population physiologically based pharmacokinetic (PBPK) model for penicillin G in heavy sows. The results showed that antemortem testing of urine provided potential correlation with tissue residue levels. Based on the United States Department of Agriculture Food Safety and Inspection Service action limit of 25 ng/g, the model estimated a withdrawal interval of 38 days for penicillin G in heavy sows after 3 repeated intramuscular injections at 5 × label dose. This study improves our understanding of penicillin G pharmacokinetics and tissue residue depletion in heavy sows and provides a tool to predict proper withdrawal intervals after extralabel use of penicillin G in heavy sows, thereby helping safety assessment of sow-derived meat products.

Comparative plasma and interstitial fluid pharmacokinetics and tissue residues of ceftiofur crystalline-free acid in cattle with induced coliform mastitis.

Ceftiofur (CEF) is a third-generation cephalosporin that is the most widely used antimicrobial in the dairy industry. Currently, violative meat residues in cull dairy cattle are commonly associated with CEF. One potential cause for violative residues is altered pharmacokinetics of the drug due to disease, which could increase the time needed for the residue to deplete. The objectives of this study were (a) to determine the absolute bioavailability of CEF crystalline-free acid (CFA) in healthy versus diseased cows; (b) to compare the plasma and interstitial fluid pharmacokinetics and plasma protein binding of CEF between healthy dairy cows and those with disease; and (c) to determine the CEF residue profile in tissues of diseased cows. For this trial, disease was induced through intramammary Escherichia coli infusion. Following disease induction and CEF CFA administration, for plasma concentrations, there was not a significant effect of treatment (p = 0.068), but the treatment-by-time interaction (p = 0.005) was significant. There was a significantly greater concentration of CEF in the plasma of the DIS cows at T2 hr (p = 0.002), T8 hr (p < 0.001), T12 hr (p = 0.001), and T16 hr (p = 0.002). For PK parameters in plasma, the slope of the terminal phase of the concentration versus time curve was significantly lower (p = 0.007), terminal half-life was significantly longer (p = 0.014), and apparent volume of distribution during the elimination phase was significantly higher (p = 0.028) diseased group. There was no difference in plasma protein binding of CEF and interstitial fluid pharmacokinetics. None of the cows had kidney CEF residues above the US tolerance level following observation of the drug's withdrawal period, but one cow with a larger apparent volume of distribution and longer terminal half-life had tissue residues slightly below the tolerance. Whereas these findings do not support the hypothesis that severely ill cows need longer withdrawal times, alterations in the terminal half-life suggest that it is theoretically possible.

Pneumatic dart delivery of tulathromycin in calves results in lower antimicrobial concentrations and increased biomarkers of stress and injection site inflammation compared with subcutaneous injection.

Remote drug delivery (RDD) using pneumatic darts has become more prevalent in situations where cattle handling facilities are not available. The objective of this study was to compare the effect of pneumatic dart delivery and subcutaneous injection of tulathromycin on plasma pharmacokinetics and biomarkers of inflammation, stress, and muscle injury in calves. Twenty-three castrated-male Holstein calves, approximately 10 mo of age with an average weight of 378 ± 6.49 kg, were randomly assigned to 1 of 2 groups. Calves in the RDD group (n = 15) received 10 mL of tulathromycin (2.42 to 2.93 mg/kg) delivered into the left neck using a Type U 10.0 mL 1.9-cm 14 G Needle pneumatic dart administered with a breech loading projector. With the exception of 1 light weight calf that received 7 mL (2.53 mg/kg), calves in the injection group (INJ) (n = 8) also received 10 mL of tulathromycin (2.34 to 2.68 mg/kg) administered as a single subcutaneous injection in the left neck using a 14 G, 1.9-cm needle and a 12-mL syringe. Serum tulathromycin, cortisol, creatine kinase (CK), and aspartate aminotransferase (AST) concentrations were determined in combination with other biomarkers of inflammation including mechanical nociceptive threshold (MNT), infrared thermography (IRT), and swelling at the injection site over 432 h after administration. Pneumatic darts failed to deliver the required dose of tulathromycin in 4 of 15 calves evidenced by heavier dart weights post-administration (24 vs. 13.5 g). When these 4 calves were removed from the analysis, calves in the RDD group were found to have a smaller area under the tulathromycin concentration curve (AUC) (P = 0.005) and faster clearance (P = 0.025) compared with the INJ group. Furthermore, the RDD group recorded a greater difference in MNT between the treated and contralateral neck compared with the INJ group at 12 h (P = 0.016), 216 h (P = 0.024), and 288 h (P = 0.0494) after administration. Serum CK was elevated at 24 h (P = 0.03) and AST was greater at 24 h (P = 0.024) and 48 h (P = 0.037) after RDD. Serum cortisol concentrations were also greater at 0.5 h (P = 0.02) after RDD. These findings suggest that RDD is associated with reduced total body exposure to tulathromycin and increased acute stress, muscle damage, and pain at the injection site. Furthermore, the failure of darts to consistently deliver antimicrobial therapy has a negative impact on the welfare of sick animals treated with RDD technologies.

Pharmacokinetics and pharmacodynamics after oral administration of tapentadol hydrochloride in dogs.

OBJECTIVE To evaluate pharmacokinetic and pharmacodynamic characteristics of 3 doses of tapentadol hydrochloride orally administered in dogs. ANIMALS 6 healthy adult mixed-breed dogs. PROCEDURES In a prospective, randomized crossover study, dogs were assigned to receive each of 3 doses of tapentadol (10, 20, and 30 mg/kg, PO); there was a 1-week washout period between subsequent administrations. Plasma concentrations and physiologic variables were measured for 24 hours. Samples were analyzed by use of high-performance liquid chromatography-tandem mass spectrometry. RESULTS Tapentadol was rapidly absorbed after oral administration. Mean maximum plasma concentrations after 10, 20, and 30 mg/kg were 10.2, 19.7, and 31 ng/mL, respectively. Geometric mean plasma half-life of the terminal phase after tapentadol administration at 10, 20, and 30 mg/kg was 3.5 hours (range, 2.7 to 4.5 hours), 3.7 hours (range, 3.1 to 4.0 hours), and 3.7 hours (range, 2.8 to 6.5 hours), respectively. Tapentadol and its 3 quantified metabolites (tapentadol sulfate, tapentadol-O-glucuronide, and desmethyltapentadol) were detected in all dogs and constituted 0.16%, 2.8%, 97%, and 0.04% of the total area under the concentration-time curve (AUC), respectively. Plasma AUCs for tapentadol, tapentadol sulfate, and tapentadol-O-glucuronide increased in a dose-dependent manner. Desmethyltapentadol AUC did not increase in a linear manner at the 30-mg/kg dose. Sedation scores and heart and respiratory rates were not significantly affected by dose or time after administration. CONCLUSIONS AND CLINICAL RELEVANCE Oral administration of tapentadol was tolerated well, and the drug was rapidly absorbed. Adverse events were not apparent in any dogs at any doses in this study.

PHARMACOKINETIC PROPERTIES OF A SINGLE ADMINISTRATION OF ORAL GABAPENTIN IN THE GREAT HORNED OWL (BUBO VIRGINIANUS).

Gabapentin (1-[aminomethyl] cyclohexane acetic acid) is a γ-aminobutyric acid analogue that has been shown to be efficacious for neuropathic pain control in humans. Plasma gabapentin concentrations >2 µg/ml are considered effective in treating epilepsy in humans and are suggested to provide analgesia for neuropathic pain. This study investigated the pharmacokinetics of a single oral dose of gabapentin suspension (11 mg/kg) in great horned owls ( Bubo virginianus ). Plasma gabapentin concentrations were determined in six healthy birds for 48 hr using high-performance liquid chromatography with mass spectrometric detection. Plasma gabapentin concentrations were estimated by noncompartmental pharmacokinetic analysis. The harmonic mean (±SD) maximum concentration (Cmax), time to maximum concentration (Tmax), and elimination half-life (tv2λZ) for gabapentin (11 mg/kg) were 6.17±0.83 µg/ml, 51.43±5.66 min, and 264.60±69.35 min, respectively. In this study, plasma gabapentin concentrations were maintained above 2 µg/ml for 528 min (8.8 hr), suggesting that gabapentin administered orally every 8 hr may be appropriate in great horned owls.

Impact of transmammary-delivered meloxicam on biomarkers of pain and distress in piglets after castration and tail docking.

To investigate a novel route for providing analgesia to processed piglets via transmammary drug delivery, meloxicam was administered orally to sows after farrowing. The objectives of the study were to demonstrate meloxicam transfer from sows to piglets via milk and to describe the analgesic effects in piglets after processing through assessment of pain biomarkers and infrared thermography (IRT). Ten sows received either meloxicam (30 mg/kg) (n = 5) or whey protein (placebo) (n = 5) in their daily feedings, starting four days after farrowing and continuing for three consecutive days. During this period, blood and milk samples were collected at 12-hour intervals. On Day 5 after farrowing, three boars and three gilts from each litter were castrated or sham castrated, tail docked, and administered an iron injection. Piglet blood samples were collected immediately before processing and at predetermined times over an 84-hour period. IRT images were captured at each piglet blood collection point. Plasma was tested to confirm meloxicam concentrations using a validated high-performance liquid chromatography-mass spectrometry method. Meloxicam was detected in all piglets nursing on medicated sows at each time point, and the mean (± standard error of the mean) meloxicam concentration at castration was 568.9±105.8 ng/mL. Furthermore, ex-vivo prostaglandin E2 (PGE2) synthesis inhibition was greater in piglets from treated sows compared to controls (p = 0.0059). There was a time-by-treatment interaction for plasma cortisol (p = 0.0009), with meloxicam-treated piglets demonstrating lower cortisol concentrations than control piglets for 10 hours after castration. No differences in mean plasma substance P concentrations between treatment groups were observed (p = 0.67). Lower cranial skin temperatures on IRT were observed in placebo compared to meloxicam-treated piglets (p = 0.015). This study demonstrates the successful transfer of meloxicam from sows to piglets through milk and corresponding analgesia after processing, as evidenced by a decrease in cortisol and PGE2 levels and maintenance of cranial skin temperature.

Pharmacokinetics of flunixin meglumine in mature swine after intravenous, intramuscular and oral administration.

BACKGROUND: The purpose of this study was to determine intravenous (IV), intramuscular (IM) and oral (PO) FM PK in mature swine. Appropriate pain management for lameness in swine is a critical control point for veterinarians and producers, but science-based guidance on optimal housing, management and treatment of lameness is deficient. Six mature swine (121-168 kg) were administered an IV, IM, or PO dose of flunixin meglumine at a target dose of 2.2 mg/kg in a cross-over design with a 10 day washout period between treatments. Plasma samples collected up to 48 hours post-administration were analyzed by high pressure liquid chromatography and mass spectrometry (HPLC-MS) followed by non-compartmental pharmacokinetic analysis. RESULTS: No adverse effects were observed with flunixin meglumine administration for all routes. Flunixin meglumine was administered at an actual mean dose of 2.21 mg/kg (range: 2.05-2.48 mg/kg) IV, IM and PO. A mean peak plasma concentration (CMAX) for IM and PO administration was 3748 ng/ml (range: 2749-6004 ng/ml) and 946 ng/ml (range: 554-1593 ng/ml), respectively. TMAX was recorded at 1.00 hour (range: 0.50-2.00 hours) and 0.61 hours (range: 0.17-2.00 hours) after PO and IM administration. Half-life (T ½ λz) for IV, IM and PO administration was 6.29 hours (range: 4.84-8.34 hours), 7.49 hours (range: 5.55-12.98 hours) and 7.08 hours (range: 5.29-9.15 hours) respectively. In comparison, bioavailability (F) for PO administration was 22% (range: 11-44%) compared to IM F at 76% (range: 54-92%). CONCLUSIONS: The results of the present study suggest that FM oral administration is not the most effective administration route for mature swine when compared to IV and IM. Lower F and Cmax of PO-FM in comparison to IM-FM suggest that PO-FM is less likely to be an effective therapeutic administration route.

Bioavailability and pharmacokinetics of oral meloxicam in llamas.

BACKGROUND: South American camelids in the United States have rapidly developed into an important agricultural industry in need of veterinary services. Pain management is challenging in camelids because there are no drugs currently approved by the U.S. Food and Drug Administration for use in these species. Dosage regimens used for many therapeutic drugs have been extrapolated from other ruminants; however, the pharmacokinetics, in camelids, may differ from those of other species. Studies investigating the pharmacokinetics of cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drugs in camelids are deficient in the published literature. Six adult llamas (121- 168 kg) were administered either a 1 mg/kg dose of oral or a 0.5 mg/kg dose of IV meloxicam in a randomized cross-over design with an 11 day washout period between treatments. Plasma samples collected up to 96 hours post-administration were analyzed by high pressure liquid chromatography and mass spectrometry detection (HPLC-MS) followed by non-compartmental pharmacokinetic analysis. RESULTS: A mean peak plasma concentration (CMAX) of 1.314 µg/mL (Range: 0.826 - 1.776 µg/mL) was recorded at 21.4 hours (Range: 12.0 - 24.0 hours) with a half-life (T ½ λz) of 22.7 hours (Range: 18.0 - 30.8 hours) after oral meloxicam administration. In comparison, a half-life (T ½ λz) of 17.4 hours (Range: 16.2 - 20.7 hours) was demonstrated with IV meloxicam administration. The oral bioavailability (F) of meloxicam (dose normalized) was 76% (Range: 48 - 92%). No adverse effects associated with either treatment modality were observed in the llamas. CONCLUSIONS: The mean bioavailability (F) of oral meloxicam was 76% indicating a high degree of gastrointestinal absorption. Plasma meloxicam concentrations >0.2 µg/mL were maintained for up to 72 h after oral administration; >0.2 µg/mL is considered to be the concentration of meloxicam required for analgesic effects in other species such as the horse. These data suggest that a single dosage of oral meloxicam at 1 mg/kg could potentially maintain therapeutic concentrations in plasma for up to 3 days in adult llamas.