Plasma and interstitial fluid antibiotic levels of subcutaneously implanted compounded florfenicol calcium sulfate beads in New Zealand White rabbits (Oryctolagus cuniculus).

OBJECTIVE: To determine antibiotic levels in plasma and interstitial fluid (ISF) after SC placement of compounded florfenicol (FF) calcium sulfate beads (CSBs) in New Zealand White rabbits (Oryctolagus cuniculus). ANIMALS: 6 juvenile female rabbits (n = 5 treatment and 1 control). METHODS: An ultrafiltration probe and CSBs were placed SC in 6 rabbits (n = 5 for FF CSBs and 1 for control CSBs). Plasma (3, 6, 12, 24, and 48 hours and 7, 14, and 21 days) and ISF (daily for 21 days) samples were collected, and FF was measured by HPLC for pharmacokinetic analysis. Hematology, biochemistry, and histopathology were assessed. RESULTS: Means ± SD for the area under the curve, maximum concentration, time of maximum concentration, terminal half-life, and mean residence time to the last data point for plasma and ISF were 16.63 ± 8.16 and 17,902 ± 7,564 h·µg/mL, 0.79 ± 0.38 and 245 ± 223 µg/mL, 2.90 ± 0.3 and 59 ± 40 hours, 30.81 ± 16.9 and 27.3 ± 9.39 hours, 23.4 ± 10 and 73.7 ± 13 hours, respectively. Plasma FF was < 2 µg/mL at all time points. The ISF FF remained > 8 µg/mL for 109.98 to 231.58 hours. One rabbit death occurred during treatment, but the cause of death was undetermined. Local tissue inflammation was present, but no clinically significant systemic adverse effects were found on hematology, biochemistry, or histopathology in the remaining rabbits. CLINICAL RELEVANCE: Florfenicol CSBs maintained antibiotic concentrations in ISF at levels likely to be effective against bacteria sensitive to > 8 µg/mL for 5 to 10 days while maintaining low (< 2 µg/mL) plasma levels. Florfenicol CSBs may be effective for local antibiotic treatment in rabbit abscesses.

SINGLE-DOSE, MULTIPLE-DOSE, AND THERAPEUTIC DRUG MONITORING PHARMACOKINETICS OF FIROCOXIB IN ASIAN ELEPHANTS (ELEPHAS MAXIMUS).

Firocoxib is a COX-2-selective nonsteroidal anti-inflammatory drug (NSAID) with limited effects on COX-1, which means it likely has fewer side effects than typically associated with other NSAIDs. This study determined possible doses of firocoxib based on single- and multidose pharmacokinetic trials conducted in 10 Asian elephants (Elephas maximus). Initially, two single oral dose trials (0.01 and 0.1 mg/kg) of a commercially available tablet (n = 6) and paste (n = 4) formulation were used to determine a preferred dose. The 0.1 mg/kg dose was further evaluated via IV single dose (n = 3) and oral multidose trials (tablets n = 6; paste n = 4). Serum peak and trough firocoxib concentrations were also evaluated in Asian elephants (n = 4) that had been being treated for a minimum of 90 consecutive days. Key pharmacokinetic parameters for the 0.1 mg/kg single-dose trials included mean peak serum concentrations of 49 ± 3.3 ng/ml for tablets and 62 ± 14.8 ng/ml for paste, area under the curve (AUC) of 1,332 ± 878 h*mg/ml for tablets and 1,455 ± 634 h*mg/ml for paste, and half-life (T1/2) of 34.3 ± 30.3 h for tablets and 19.9 ± 12.8 h for paste. After 8 d of dosing at 0.1 mg/kg every 24 h, pharmacokinetic parameters stabilized to an AUC of 6,341 ± 3,003 h*mg/ml for tablets and 5,613 ± 2,262 for paste, and T1/2 of 84.4 ± 32.2 h for tablets and 62.9 ± 2.3 h for paste. Serum COX inhibition was evaluated in vitro and ex vivo in untreated elephant plasma, where firocoxib demonstrated preferential inhibition of COX-2. No adverse effects from firocoxib administration were identified in this study. Results suggest administering firocoxib to Asian elephants at a dose of 0.1 mg/kg orally, using either tablet or paste formulations, every 24 h.

Pharmacokinetics of mebendazole in plasma and cerebrospinal fluid following a single oral dose in healthy dogs.

Novel therapies are needed for treatment of gliomas. Mebendazole previously demonstrated anti-neoplastic effects on canine glioma cell lines at in vitro mean inhibitory concentrations (IC50) of 10 ng/mL. Our study aimed to titrate the oral dose of mebendazole necessary to achieve concentrations ≥10 ng/mL in cerebrospinal fluid (CSF) of healthy dogs. We hypothesized that an oral dose up to 200 mg/kg would be necessary. Phase one was a dose titration study using a total of 6 mixed breed dogs that described dose vs. plasma concentrations for 72 h after single oral dosing of either 50 mg/kg (n = 2), 100 mg/kg (n = 2), or 200 mg/kg (n = 2). Based on phase one, phase two dogs (total of 9) received 100 mg/kg (n = 4) or 200 mg/kg (n = 5) orally and blood samples were collected intermittently for 60 h with CSF samples collected intermittently for 24 h. Mebendazole was quantitated in plasma and CSF using high performance liquid chromatography. Median peak plasma concentrations (Cmax) were reached at 7 ± 2 h (100 mg/kg) of 220 ng/mL (81, 283) and at 15 ± 4 h (200 mg/kg) of 147 ng/ml (112, 298). The respective area under the curve (AUC: ng/ml/h) reported as a median was 2,119 (1,876, 3,288) vs. 3,115 (1,559, 4,972). Median plasma concentrations (ng/ml) for 100 vs. 200 mg/kg were 47 (32, 52) vs. 65 (35, 104), respectively. For CSF, the median value for Cmax (at 100 mg/kg vs. 200 mg/kg) was 8 (2, 28) vs. 21 (12, 27) and AUC was 87 (22, 157) vs. 345 (92, 372), respectively. Relative bioavailability in CSF vs. plasma was 4 to 10%. Although several animals demonstrated clinical signs indicative of gastrointestinal upset [i.e., vomiting (n = 2), diarrhea (n = 2), or both (n = 1)], these events were not considered serious. The in vitro IC50 for gliomas can be reached in CSF at 100 mg/kg (n = 1), however a 200 mg/kg dose yielded more consistent concentrations.

SERUM DISPOSITION OF A SINGLE DOSE OF ORALLY ADMINISTERED FIROCOXIB IN AFRICAN ELEPHANTS (LOXODONTA AFRICANA).

The time course of serum firocoxib concentrations was described after administration of two single oral doses (0.01 and 0.1 mg/kg) of commercially available firocoxib tablet (n = 4) and paste (n = 2) formulations to six healthy adult female African (Loxodonta africana) elephants. Firocoxib was quantitated by high-performance liquid chromatography. Firocoxib serum concentrations were below detectable levels after administration of 0.01 mg/kg of both formulations. A dose of 0.1 mg/kg (n = 4) of the tablet formulation had the following mean ± SD of pharmacokinetic parameters: area under the curve (AUC) 1,588 ± 362 h × ng/ml, maximum plasma concentration (Cmax) 31 ± 6.6 ng/ml at 6.4 ± 1.8 h, and disappearance half-life (T1/2) 66 ± 59 h, Elephant compliance to oral administration of the paste formulation was challenging, with only two elephants accepting administration of the paste at 0.1 mg/kg. Pharmacokinetic parameters determined included AUC of 814 h × ng/ml, Cmax of 44 ng/ml at Tmax of 7.0 h, and T1/2 of 36.4 h. Based on mean AUC, the relative bioavailability of paste compared to tablet formulations was 50%. Limitations of this study were the small number of participants and elephant compliance with the paste formulation. This study supports an oral dose of 0.1 mg/kg every 24 h. Multidose and IV trials are indicated to confirm firocoxib dosing requirements for African elephants.

Disposition of a single oral dose of a cannabidiol medication in healthy cats.

The historical use of the marijuana plant for medicinal purposes is long. One of the historical uses has been for the treatment of epilepsy. Recently, the Food and Drug Administration has approved a highly purified cannabidiol medication for the add on therapy in people with certain forms of epilepsy. With the increase interest of the use of cannabidiol in the veterinary community, the aim of this study was to describe the disposition of a single dose of a cannabidiol medication in healthy cats in both the fed and fasted state. Pharmacokinetic analysis reveals that relative bioavailability of cannabidiol shows a near eleven-fold increase when administered in the fed state compared to the fasted state. Additionally, concentrations achieved at a dose of 5 mg/kg, may be sufficient to explore the therapeutic potential in cats with epilepsy.

PHARMACOKINETICS OF PRIMAQUINE PHOSPHATE AFTER A SINGLE ORAL ADMINISTRATION TO AFRICAN PENGUINS (SPHENISCUS DEMERSUS).

Primaquine is an 8-aminoquinolone drug commonly used for the chemoprophylaxis and treatment of avian malarial infections in managed penguin populations worldwide. Little is known about its pharmacokinetic properties in avian species. The objective of this study was to describe the disposition of primaquine phosphate after a single oral dose in 15 healthy African penguins (Spheniscus demersus). A single tablet containing 26.3 mg of primaquine phosphate (equivalent to 15 mg primaquine base) was administered orally to each bird in a herring fish. Blood samples were collected prior to drug administration and at predetermined timepoints through 144 hr postadministration. Plasma was analyzed for drug concentration by high-performance liquid chromatography with ultraviolet detection. Mean maximum plasma concentration of primaquine phosphate was 277 ± 96 ng/ml at approximately 3.1 hr following oral administration. The mean disappearance half-life was 3.6 ± 1.6 hr. Plasma concentrations were below detectable limits in all but one penguin by 36 hr. A single oral administration of 26.3 mg of primaquine phosphate in African penguins resulted in a pharmacokinetic profile comparable to those attained in human studies. These results suggest that a dosing interval similar to human regimens may be of potential use in the prevention and treatment of avian malaria in penguins. Additional clinical studies are needed to determine the efficacy and safety of this regimen.

Pharmacokinetics of Pimobendan and Its Metabolite O-Desmethyl-Pimobendan Following Rectal Administration to Healthy Dogs.

Objective: This study describes the pharmacokinetics of parent pimobendan (PIM) and its active metabolite, o-desmethyl-pimobendan (ODMP), after oral and rectal administration of pimobendan to healthy dogs. Animals: A total of eight healthy privately owned dogs were used in this study. Procedures: The dogs received a single dose (0.5 mg/kg) of a commercially available pimobendan tablet per os (PO). Twelve blood samples were collected over a 12-h period for pharmacokinetic analysis. After a 24-h washout period, the dogs received the same dose of pimobendan solution per rectum (PR), and samples were obtained at the same time for analysis. Results: For PIM, PO vs. PR, respectively, the mean maximum plasma concentration (C max, ng/ml) was 49.1 ± 28.7 vs. 10.1 ± 2, the time to reach a maximum concentration (T max, h) was 2.1 ± 0.9 vs. 1 ± 0.4, the disappearance half-life (t 1/2, h) was 1.8 ± 0.8 vs. 2.2 ± 0.6, and the area under the concentration-time curve (AUC, ng*h/ml) was 148.4 ± 71.6 vs. 31.1 ± 11.9, with relative bioavailability (F, %) of 25 ± 8. For ODMP, PO vs. PR, respectively, C max was 30.9 ± 10.4 vs. 8.8 ± 4.8, T max was 3.2 ± 1.6 vs. 1.7 ± 1.1, and t 1/2 was 5.0 ± 2.7 vs. 8.3 ± 4.8, with AUC of 167.8 ± 36.2 vs. 50.1 ± 19.2 and F of 28 ± 6. The differences between PO and PR were significant (P < 0.03) for AUC and C max for both PIM and ODMP. Conclusions and Clinical Relevance: The pharmacokinetics of PIM and ODMP were described following PO and PR administration. The findings suggest that pimobendan PR might achieve effective concentrations and, as such, warrant future studies of clinical effectiveness in treating dogs with congestive heart failure and which are unable to receive medication PO.

Regulation of the neuroendocrine axis in male rats by soy-based diets is independent of age and due specifically to isoflavone action†.

Soy-based foods are consumed for their health beneficial effects, implying that the population is exposed to soy isoflavones in the diet. Herein, male rats at 21, 35, and 75 days of age were maintained either on a casein control diet, soybean meal (SBM), or control diet supplemented with daidzin and genistin (G + D) for 14 days. Feeding of SBM and G + D diets decreased testicular testosterone (T) secretion regardless of age. Altered androgen secretion was due to decreased (P < 0.05) Star and Hsd17ß protein in the testes and was associated with increased (P < 0.05) Lhß and Fshß subunit protein expression in pituitary glands. Second, male rats were fed either a casein control diet, control diet + daidzin, control diet + genistin, or control diet + genistin + daidzin (G + D). Compared to control, feeding of all isoflavone-containing diets decreased (P < 0.05) testicular T concentrations, and more so in the G + D diet group. Interestingly, Esr1 and androgen receptor protein and pituitary Fshß with Lhß subunit protein were increased (P < 0.05) by feeding of genistin and G + D diets, but not the daidzin diet. However, daidzein and genistein both caused a concentration dependent inhibition (P < 0.05) of T secretion by Leydig cells in vitro with IC50 of 184 ηM and 36 ηM, respectively. Results demonstrated that altered testicular steroidogenic capacity and pituitary FSHß and LHß subunit expression due to soy-based diets result from specific actions by genistein and daidzein. Experiments to assess effects of isoflavone regulation of intratesticular androgen concentrations on male fertility are warranted.

Effects of oral administration of 5 immunosuppressive agents on activated T-cell cytokine expression in healthy dogs.

BACKGROUND: Dogs are often adminstered >1 immunosuppressive medication when treating immune-mediated diseases, and determining whether these different medications affect IL-2 expression would be useful when performing pharmacodynamic monitoring during cyclosporine therapy. HYPOTHESIS/OBJECTIVES: To determine the effects of 5 medications (prednisone, cyclosporine, azathioprine, mycophenolate mofetil, and leflunomide) on activated T-cell expression of the cytokines IL-2 and interferon-gamma (IFN-γ). ANIMALS: Eight healthy dogs. METHODS: Randomized, cross-over study comparing values before and after treatment, and comparing values after treatment among drugs. Dogs were administered each drug at standard oral doses for 1 week, with a washout of at least 21 days. Activated T-cell expression of IL-2 and IFN-γ mRNA was measured by quantitative reverse transcription polymerase chain reaction. Blood drug concentrations were measured for cyclosporine, mycophenolate, and leflunomide metabolites. RESULTS: Least squares means (with 95% confidence interval) before treatment for IL-2 (2.91 [2.32-3.50] ΔCt) and IFN-γ (2.33 [1.66-3.00 ΔCt]) values were significantly lower (both P < .001) than values after treatment (10.75 [10.16-11.34] and 10.79 [10.11-11.46] ΔCt, respectively) with cyclosporine. Similarly, least squares means before treatment for IL-2 (1.55 [1.07-2.02] ΔCt) and IFN-γ (2.62 [2.32-2.92] ΔCt) values were significantly lower (both P < .001) than values after treatment (3.55 [3.06-4.00] and 5.22 [4.92-5.52] ΔCt, respectively) with prednisone. Comparing delta cycle threshold values after treatment among drugs, cyclosporine was significantly different than prednisone (IL-2 and IFN-γ both P < .001), with cyclosporine more suppressive than prednisone. CONCLUSIONS AND CLINICAL IMPORTANCE: Prednisone and cyclosporine both affected expression of IL-2 and IFN-γ, suggesting that both have the ability to influence results when utilizing pharmacodynamic monitoring of cyclosporine treatment.

Quality assessment of fluconazole capsules and oral suspensions compounded by pharmacies located in the United States.

OBJECTIVE To evaluate pharmaceutical characteristics (strength or concentration, accuracy, and precision), physical properties, and bacterial contamination of fluconazole compounded products. SAMPLE Fluconazole compounded products (30- and 240-mg capsules; 30- and 100-mg/mL oral suspensions) from 4 US veterinary compounding pharmacies. PROCEDURES Fluconazole compounded products were ordered 3 times from each of 4 pharmacies at 7- or 10-day intervals. Generic fluconazole products (50- and 200-mg tablets; 10- and 40-mg/mL oral suspensions) served as references. Compounded products were evaluated at the time of receipt; suspensions also were evaluated 3 months later and at beyond-use dates. Evaluations included assessments of strength (concentration), accuracy, precision, physical properties, and bacterial contamination. Acceptable accuracy was defined as within ± 10% of the labeled strength (concentration) and acceptable precision as within ± 10%. Fluconazole was quantified by use of high-performance liquid chromatography. RESULTS Physical characteristics of compounded products differed among pharmacies. Aerobic bacterial cultures yielded negative results. Capsules (30 and 240 mg) had acceptable accuracy (median, 96.3%; range, 87.3% to 135.2%) and precision (mean ± SD, 7.4 ± 6.0%). Suspensions (30 and 100 mg/mL) had poor accuracy (median, 73.8%; range, 53.9% to 95.2%) and precision (mean ± SD, 15.0 ± 6.9%). Accuracy and precision were significantly better for capsules than for suspensions. CONCLUSIONS AND CLINICAL RELEVANCE Fluconazole compounded products, particularly suspensions, differed in pharmaceutical and physical qualities. Studies to evaluate the impact of inconsistent quality on bioavailability or clinical efficacy of compounded fluconazole products are indicated, and each study should include data on the quality of the compounded product evaluated.

Determining canine skin concentrations of terbinafine to guide the treatment of Malassezia dermatitis.

BACKGROUND: Terbinafine (TBF) is known to concentrate and persist in human skin. Its use is increasing in veterinary medicine, but there are limited data concerning its tissue concentration and efficacy in dogs. HYPOTHESIS/OBJECTIVES: (i) Describe TBF accumulation in canine skin; (ii) Integrate pharmacokinetic data with historical minimum inhibitory concentration (MIC) results for Malassezia pachydermatis to verify the currently used dosage of TBF for the treatment of Malassezia dermatitis. ANIMALS: Ten healthy, client-owned dogs. METHODS: Dogs were given TBF (generic preparation, 250 mg tablets) 30 mg/kg per os (p.o.) once daily for 21 days. Serum, sebum and stratum corneum (SC) samples were collected on days 1, 5, 7, 11, 14, 21, 28 and 35. High-pressure liquid chromatography was used to determine drug concentrations in samples. RESULTS: Relevant (mean ± standard deviation) parameters for TBF in serum, paw SC, thorax SC and sebum, respectively, were: maximum concentration (Cmax , µg/mL) 23.59 ± 10.41, 0.31 ± 0.26, 0.30 ± 0.32 and 0.48 ± 0.25; half-life (t1/2 , d) 4.49 ± 2.24, 6.34 ± 5.33, 4.64 ± 3.27 and 5.12 ± 3.33; time to maximum concentration (Tmax , d) 10.40 ± 6.98, 13.20 ± 5.16, 11.90 ± 8.62 and 10.60 ± 3.69. CONCLUSIONS AND CLINICAL IMPORTANCE: These results suggest that TBF does not achieve high concentrations in canine SC or sebum compared to serum. The mean Cmax of all skin tissues (paw SC, thorax SC and sebum) barely exceeded the reported Malassezia MIC90, of 0.25 µg/mL, which indicates that doses higher than 30 mg/kg p.o. once daily may be necessary.

Voriconazole Disposition After Single and Multiple, Oral Doses in Healthy, Adult Red-tailed Hawks ( Buteo jamaicensis ).

Voriconazole is effective for treatment of aspergillosis, a common disease in captive red-tailed hawks ( Buteo jamaicensis ). To determine the disposition and safety of voriconazole after single and multiple, oral doses, 12 adult red-tailed hawks were studied in 2 phases. In phase 1, each bird received a single dose of voriconazole solution (10 mg/kg) by gavage. Blood samples were collected at 0, 0.5, 1, 3, 6, 9, 12, 16, 24, and 36 hours after treatment. In phase 2, each of 8 birds received voriconazole oral solution at 10 mg/kg PO q12h for 14 days. Plasma samples were collected on days 0, 5, and 10 and after the final dose and were processed as in phase 1. Plasma samples were submitted for analysis of voriconazole levels by high-performance liquid chromatography and ultraviolet spectrophotometry and for measurement of selected plasma biochemical parameters. After single dosing, voriconazole concentrations reached a (mean ± SD) peak (Cmax) of 4.7 ± 1.3 µg/mL at 2.0 ± 1.2 hours. The disappearance half-life (t1/2) was 2.8 ± 0.7 hours, and the mean residence time (MRT) was 4.6 ± 0.9 hours. After the last dose at 14 days, the mean Cmax of voriconazole was 4.5 ± 2.7 µg/mL at 2.4 ± 1.1 hours. The t1/2 was 2.1 ± 0.8 hours, and the MRT was 3.5 ± 1.1 hours. Although concentrations of several plasma biochemical parameters were significantly different at study end compared with prestudy concentrations, only plasma creatine kinase activity was outside the reference range. No adverse reactions were observed in any of the birds. After both single and multiple dosing at 10 mg/kg, voriconazole concentrations exceeded the minimum inhibitory concentration to inhibit 90% (MIC90) of Aspergillus species (1 µg/mL) by at least fourfold and remained above the MIC90 for 8.8 ± 1.1 hours after single dosing versus 6.5 ± 1.5 hours after multiple dosing (P = .003). This difference suggests that more frequent dosing (eg, up to q8h) may be necessary to maintain target concentrations during prolonged therapy.

Accuracy and precision of compounded ciclosporin capsules and solution.

BACKGROUND: The prescribing of compounded products that mimic US Federal Drug Administration approved drugs in the USA is inappropriate. Among the reasons are the lack of premarket regulatory assessment and the potential for an inferior product. This study describes the accuracy and precision of ciclosporin (CsA) strength when compounded as capsules (10 and 300 mg) and solutions (50 and 150 mg/mL). METHODS: Preparation choices reflected current prescribing practices. Each was acquired by prescription from five pharmacies at three different times, 14-45 days apart. Atopica(®) (10 and 100 mg; Novartis, Greensboro, NC, USA) and three human generics (50 and 100 mg capsules and 100 mg/mL solution) were positive controls. Physical characteristics were assessed. Accuracy (percentage predicted) was based on CsA strength measured by high-performance liquid chromatography and precision was based on replications (n = 3) from each pharmacy. RESULTS: Accuracy of positive controls ranged from 92 to 103%. For compounded solutions, physical characteristics differed markedly between but not within pharmacies. Capsule accuracy was 10 ± 0.98 mg (101%) for 10 mg and 290 ± 9.6 mg (97%) for 300 mg; and solution accuracy was 45 ± 9.9 mg/mL (90%) for 50 mg/mL and 127 ± 18 mg/mL (85%) for 150 mg/mL. The precision for 50 mg/mL oral solution was 0.67-11%, and for 150 mg/mL, 3.7-14%. Accuracy for all preparations varied, with the least accurate deviating by 34% from labelled strength. Precision for all capsules ranged from 0.6 to 8.7%. CONCLUSIONS AND CLINICAL IMPORTANCE: Compounded CsA solutions may deviate by more than 10% from the labelled strength. Bioavailability and clinical efficacy of compounded CsA remain unknown, and such products should be prescribed only in appropriate circumstances.

Antiviral treatment of calves persistently infected with bovine viral diarrhoea virus.

BACKGROUND: Animals persistently infected (PI) with bovine viral diarrhoea virus (BVDV) are a key source of viral propagation within and among herds. Currently, no specific therapy exists to treat PI animals. The purpose of this research was to initiate evaluation of the pharmacokinetic and safety data of a novel antiviral agent in BVDV-free calves and to assess the antiviral efficacy of the same agent in PI calves. METHODS: One BVDV-free calf was treated with 2-(2-benzimidazolyl)-5-[4-(2-imidazolino)phenyl]furan dihydrochloride (DB772) once at a dose of 1.6 mg/kg intravenously and one BVDV-free calf was treated three times a day for 6 days at 9.5 mg/kg intravenously. Subsequently, four PI calves were treated intravenously with 12 mg/kg DB772 three times a day for 6 days and two PI control calves were treated with an equivalent volume of diluent only. RESULTS: Prior to antiviral treatment, the virus isolated from each calf was susceptible to DB772 in vitro. The antiviral treatment effectively inhibited virus for 14 days in one calf and at least 3 days in three calves. Subsequent virus isolated from the three calves was resistant to DB772 in vitro. No adverse effects of DB772 administration were detected. CONCLUSIONS: Results demonstrate that DB772 administration is safe and exhibits antiviral properties in PI calves while facilitating the rapid development of viral resistance to this novel therapeutic agent.

Pharmacokinetics of tramadol and metabolites O-desmethyltramadol and N-desmethyltramadol in adult horses.

OBJECTIVE: To determine the pharmacokinetics of tramadol and its metabolites O-desmethyltramadol (ODT) and N-desmethyltramadol (NDT) in adult horses. ANIMALS: 12 mixed-breed horses. PROCEDURES: Horses received tramadol IV (5 mg/kg, over 3 minutes) and orally (10 mg/kg) with a 6-day washout period in a randomized crossover design. Serum samples were collected over 48 hours. Serum tramadol, ODT, and NDT concentrations were measured via high-performance liquid chromatography and analyzed via noncompartmental analysis. RESULTS: Maximum mean ± SEM serum concentrations after IV administration for tramadol, ODT, and NDT were 5,027 ± 638 ng/mL, 0 ng/mL, and 73.7 ± 12.9 ng/mL, respectively. For tramadol, half-life, volume of distribution, area under the curve, and total body clearance after IV administration were 2.55 ± 0.88 hours, 4.02 ± 1.35 L/kg, 2,701 ± 275 h x ng/mL, and 30.1 ± 2.56 mL/min/kg, respectively. Maximal serum concentrations after oral administration for tramadol, ODT, and NDT were 238 ± 41.3 ng/mL, 86.8 ± 17.8 ng/mL, and 159 ± 20.4 ng/mL, respectively. After oral administration, half-life for tramadol, ODT, and NDT was 2.14 ± 0.50 hours, 1.01 ± 0.15 hours, and 2.62 ± 0.49 hours, respectively. Bioavailability of tramadol was 9.50 ± 1.28%. After oral administration, concentrations achieved minimum therapeutic ranges for humans for tramadol (> 100 ng/mL) and ODT (> 10 ng/mL) for 2.2 ± 0.46 hours and 2.04 ± 0.30 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Duration of analgesia after oral administration of tramadol might be < 3 hours in horses, with ODT and the parent compound contributing equally.