Objective: To evaluate the pharmacokinetics and pharmacodynamics of zolpidem after oral administration of a single dose (0.15 or 0.50 mg/kg) and assess any associated antianxiety and sedative effects in dogs. Animals: 8 clinically normal sexually intact male dogs of various breeds. Procedures: Dogs were assigned to 2 groups (4 dogs/group) and administered zolpidem orally once at a dose of 0.15 or 0.50 mg/kg in a crossover study; each dog received the other treatment once after an interval of 1 week. Blood samples were collected before and at intervals during the 24-hour period following dose administration. For each time point, plasma zolpidem concentration was evaluated via a validated method of high-performance liquid chromatography coupled with fluorescence detection, and pharmacodynamics were assessed via subjective assessments of sedation and level of agitation and selected clinical variables. Results: The pharmacokinetic profile of zolpidem in dogs was dose dependent, and the plasma drug concentrations attained were lower than those for humans administered equivalent doses. The lower dose did not result in any clinical or adverse effects, but the higher dose generated paradoxical CNS stimulation of approximately 1 hour's duration and a subsequent short phase of mild sedation. This sedation phase was not considered to be of clinical relevance. The desired clinical effects were not evident at plasma zolpidem concentrations ≤ 30 ng/mL, and the minimal plasma concentration that induced adverse effects was 60 ng/mL. Conclusions and Clinical Relevance: Results indicated that zolpidem is not a suitable drug for inducing sedation in dogs.

Objective: To determine pharmacokinetics after IV and oral administration of a single dose of tramadol hydrochloride to Hispaniolan Amazon parrots (Amazona ventralis). Animals: 9 healthy adult Hispaniolan Amazon parrots (3 males, 5 females, and 1 of unknown sex). Procedures: Tramadol (5 mg/kg, IV) was administered to the parrots. Blood samples were collected from −5 to 720 minutes after administration. After a 3-week washout period, tramadol (10 and 30 mg/kg) was orally administered to parrots. Blood samples were collected from −5 to 1,440 minutes after administration. Three formulations of oral suspension (crushed tablets in a commercially available suspension agent, crushed tablets in sterile water, and chemical-grade powder in sterile water) were evaluated. Plasma concentrations of tramadol and its major metabolites were measured via high-performance liquid chromatography. Results: Mean plasma tramadol concentrations were > 100 ng/mL for approximately 2 to 4 hours after IV administration of tramadol. Plasma concentrations after oral administration of tramadol at a dose of 10 mg/kg were < 40 ng/mL for the entire time period, but oral administration at a dose of 30 mg/kg resulted in mean plasma concentrations > 100 ng/mL for approximately 6 hours after administration. Oral administration of the suspension consisting of the chemical-grade powder resulted in higher plasma tramadol concentrations than concentrations obtained after oral administration of the other 2 formulations; however, concentrations differed significantly only at 120 and 240 minutes after administration. Conclusions and Clinical Relevance: Oral administration of tramadol at a dose of 30 mg/kg resulted in plasma concentrations (> 100 ng/mL) that have been associated with analgesia in Hispaniolan Amazon parrots.

Objective: To determine the pharmacokinetics of a commercial formulation of doxycycline hyclate after IM administration of a single dose to sheep. Animals: 11 healthy domestic sheep. Procedures: For each sheep, doxycycline was administered as a single dose of 20 mg/kg, IM. Blood samples were obtained prior to and for 84 hours after doxycycline administration. Plasma concentrations of doxycycline were determined via high-performance liquid chromatography with UV detection. Pharmacokinetic data were analyzed with noncompartmental methods. Results: Mean ± SD values for pharmacokinetic parameters included maximum plasma concentration (2.792 ± 0.791 μg/mL), time to reach maximum plasma concentration (0.856 ± 0.472 hours), mean residence time (91.1 ± 40.78 hours), elimination half-life (77.88 ± 28.45 hours), and area under the curve (65.67 ± 9.877 μg•h/mL). Conclusions and Clinical Relevance: Results indicated that doxycycline had prolonged absorption and elimination in sheep after IM administration. A daily dose of 20 mg/kg would be sufficient to reach effective plasma concentrations against Chlamydia spp (minimum inhibitory concentration, 0.008 to 0.031 μg/mL) and Staphylococcus aureus (minimum inhibitory concentration, 0.12 μg/mL). Doxycycline administered IM could be an option for therapeutic use in sheep, although further studies are needed.

Objective: To determine the pharmacokinetic properties of 1 IM injection of ceftiofur crystalline-free acid (CCFA) in American black ducks (Anas rubripes). Animals: 20 adult American black ducks (6 in a preliminary experiment and 14 in a primary experiment). Procedures: Dose and route of administration of CCFA for the primary experiment were determined in a preliminary experiment. In the primary experiment, CCFA (10 mg/kg, IM) was administered to ducks. Ducks were allocated into 2 groups, and blood samples were obtained 0.25, 0.5, 1, 2, 4, 8, 12, 48, 96, 144, 192, and 240 hours or 0.25, 0.5, 1, 2, 4, 8, 24, 72, 120, 168, and 216 hours after administration of CCFA. Plasma concentrations of ceftiofur free acid equivalents (CFAEs) were determined by use of high-performance liquid chromatography. Data were evaluated by use of a naive pooled-data approach. Results: The area under the plasma concentration versus time curve from 0 hours to infinity was 783 h•μg/mL, maximum plasma concentration observed was 13.1 μg/mL, time to maximum plasma concentration observed was 24 hours, terminal phase half-life was 32.0 hours, time that concentrations of CFAEs were higher than the minimum inhibitory concentration (1.0 μg/mL) for many pathogens of birds was 123 hours, and time that concentrations of CFAEs were higher than the target plasma concentration (4.0 μg/mL) was 73.3 hours. Conclusions and Clinical Relevance: On the basis of the time that CFAE concentrations were higher than the target plasma concentration, a dosing interval of 3 days can be recommended for future multidose CCFA studies.

Objective: To compare the pharmacokinetics of a novel bioadhesive gel formulation of midazolam after intranasal (IN) administration with that of midazolam solution after IN, IV, and rectal administration to dogs. Animals: 10 (5 males and 5 females) healthy adult Beagles. Procedures: Dogs were assigned to 4 treatment groups for a crossover study design. Initially, midazolam solution (5 mg/mL) was administered (0.2 mg/kg) IV to group 1, rectally to group 2, and IN to group 3; a 0.4% hydroxypropyl methylcellulose midazolam gel formulation (50 mg/mL) was administered (0.2 mg/kg, IN) to group 4. Each dog received all 4 treatments; there was a 7-day washout period between subsequent treatments. Blood samples were collected before and after midazolam administration. Plasma concentration of midazolam was determined by use of high-performance liquid chromatography. Results: The peak plasma concentration after IN administration of the gel formulation was significantly higher than that after IN and rectal administration of the solution. Mean ± SD time to peak concentration was 11.70 ± 2.63 minutes (gel IN), 17.50 ± 2.64 minutes (solution IN), and 39 ± 14.49 minutes (solution rectally). Mean bioavailability of midazolam was 70.4% (gel IN), 52.0% (solution IN), and 49.0% (solution rectally). Bioavailability after IN administration of the gel formulation was significantly higher than that after IN and rectal administration of the solution. Conclusions and Clinical Relevance: IN administration of midazolam gel was superior to both IN and rectal administration of midazolam solution with respect to peak plasma concentration and bioavailability.

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•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.

Objective: To determine whether therapeutic concentrations of levetiracetam can be achieved in cats and to establish reasonable IV and oral dosing intervals that would not be associated with adverse effects in cats. Animals: 10 healthy purpose-bred cats. Procedures: In a randomized crossover study, levetiracetam (20 mg/kg) was administered orally and IV to each cat. Blood samples were collected 0, 10, 20, and 40 minutes and 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours after administration. Plasma levetiracetam concentrations were determined via high-performance liquid chromatography. Results: Mean ± SD peak concentration was 25.54 ± 7.97 μg/mL. The mean y-intercept for IV administration was 37.52 ± 6.79 μg/mL. Half-life (harmonic mean ± pseudo-SD) was 2.95 ± 0.95 hours and 2.86 ± 0.65 hours for oral and IV administration, respectively. Mean volume of distribution at steady state was 0.52 ± 0.09 L/kg, and mean clearance was 2.0 ± 0.60 mL/kg/min. Mean oral bioavailability was 102 ± 39%. Plasma drug concentrations were maintained in the therapeutic range reported for humans (5 to 45 μg/mL) for at least 9 hours after administration in 7 of 10 cats. Only mild, transient hypersalivation was evident in some cats after oral administration. Conclusions and Clinical Relevance: Levetiracetam (20 mg/kg) administered orally or IV to cats every 8 hours should achieve and maintain concentrations within the therapeutic range for humans. Levetiracetam administration has favorable pharmacokinetics for clinical use, was apparently tolerated well, and may be a reasonable alternative antiepileptic drug in cats.

Objective—To determine whether administration of lidocaine during ischemia and reperfusion in horses results in concentrations in smooth muscle sufficient to protect against the negative consequences of ischemia-reperfusion injury on smooth muscle motility. Animals—12 horses. Procedures—Artificial ischemia and reperfusion injury of jejunal segments was induced in vivo in conjunction with lidocaine treatment during ischemia (IRL) or without lidocaine treatment (IR). Isometric force performance was measured in vitro in IRL and IR smooth muscle preparations with and without additional in vitro application of lidocaine. Lidocaine concentrations in smooth muscle were determined by means of high-performance liquid chromatography. To assess the influence of lidocaine on membrane permeability, activity of creatine kinase and lactate dehydrogenase released by in vitro incubated tissues was determined biochemically. Results—In vivo administration of lidocaine allowed maintenance of contractile performance after an ischemia and reperfusion injury. Basic contractility and frequency of contractions were significantly increased in IRL smooth muscle tissues in vitro. Additionally, in vitro application of lidocaine achieved further improvement of contractility of IR and IRL preparations. Only in vitro application of lidocaine was able to ameliorate membrane permeability in smooth muscle of IR and IRL preparations. Lidocaine accumulation could be measured in in vivo treated samples and serum. Conclusions and Clinical Relevance—In vivo lidocaine administration during ischemia and reperfusion had beneficial effects on smooth muscle motility. Initiating lidocaine treatment during surgery to treat colic in horses may improve lidocaine's prokinetic features by protecting smooth muscle from effects of ischemia and reperfusion injury.

Objective—To evaluate the elimination pharmacokinetics of a single IM injection of a long-acting ceftiofur preparation (ceftiofur crystalline-free acid [CCFA]) in healthy adult helmeted guineafowl (Numida meleagris). Animals—14 healthy adult guineafowl. Procedures—1 dose of CCFA (10 mg/kg) was administered IM to each of the guineafowl. Blood samples were collected intermittently via jugular venipuncture over a 144-hour period. Concentrations of ceftiofur and all desfuroylceftiofur metabolites were measured in plasma via high-performance liquid chromatography. Results—No adverse effects of drug administration or blood collection were observed in any bird. The minimal inhibitory concentration (MIC) for many bacterial pathogens of poultry and domestic ducks (1 μg/mL) was achieved by 1 hour after administration in most birds and by 2 hours in all birds. A maximum plasma concentration of 5.26 μg/mL was reached 19.3 hours after administration. Plasma concentrations remained higher than the MIC for at least 56 hours in all birds and for at least 72 hours in all but 2 birds. The harmonic mean ± pseudo-SD terminal half-life of ceftiofur was 29.0 ± 4.93 hours. The mean area under the curve was 306 ± 69.3 μg•h/mL, with a mean residence time of 52.0 ± 8.43 hours. Conclusions and Clinical Relevance—A dosage of 10 mg of CCFA/kg, IM, every 72 hours in helmeted guineafowl should provide a sufficient plasma drug concentration to inhibit growth of bacteria with an MIC ≤ 1 μg/mL. Clinical use should ideally be based on bacterial culture and antimicrobial susceptibility data and awareness that use of CCFA in avian patients constitutes extralabel use of this product.

Objective—To determine the disposition of gamithromycin in plasma, pulmonary epithelial lining fluid (PELF), bronchoalveolar lavage (BAL) cells, and lung tissue homogenate in cattle. Animals—33 healthy Angus calves approximately 7 to 8 months of age. Procedures—Calves were randomly assigned to 1 of 11 groups consisting of 3 calves each, which differed with respect to sample collection times. In 10 groups, 1 dose of gamithromycin (6 mg/kg) was administered SC in the neck of each calf (0 hours). The remaining 3 calves were not treated. Gamithromycin concentrations in plasma, PELF, lung tissue homogenate, and BAL cells (matrix) were measured at various points by means of high-performance liquid chromatography with tandem mass spectrometry. Results—Time to maximum gamithromycin concentration was achieved at 1 hour for plasma, 12 hours for lung tissue, and 24 hours for PELF and BAL cells. Maximum gamithromycin concentration was 27.8 μg/g, 17.8 μg/mL, 4.61 μg/mL, and 0.433 μg/mL in lung tissue, BAL cells, PELF, and plasma, respectively. Terminal half-life was longer in BAL cells (125.0 hours) than in lung tissue (93.0 hours), plasma (62.0 hours), and PELF (50.6 hours). The ratio of matrix to plasma concentrations ranged between 4.7 and 127 for PELF, 16 and 650 for lung tissue, and 3.2 and 2,135 for BAL cells. Conclusions and Clinical Relevance—Gamithromycin was rapidly absorbed after SC administration. Potentially therapeutic concentrations were achieved in PELF, BAL cells, and lung tissue within 30 minutes after administration and persisted for 7 (PELF) to > 15 (BAL cells and lung tissue) days after administration of a single dose.