Objective—To assess pharmacokinetics and pharmacodynamics of morphine and the effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds.
Animals—6 healthy Greyhounds, 3 male and 3 female.
Procedures—Morphine sulfate (0.5 mg/kg. IV) was administered to Greyhounds prior to and after 5 days of ketoconazole (12.7 ± 0.6 mg/kg, PO) treatment. Plasma samples were obtained from blood samples that were collected at predetermined time points for measurement of morphine and ketoconazole concentrations by mass spectrometry. Pharmacokinetics of morphine were estimated by use of computer software.
Results—Pharmacodynamic effects of morphine in Greyhounds were similar to those of other studies in dogs and were similar between treatment groups. Morphine was rapidly eliminated with a half-life of 1.28 hours and a plasma clearance of 32.55 mL/min/kg. The volume of distribution was 3.6 L/kg. No significant differences in the pharmacokinetics of morphine were found after treatment with ketoconazole. Plasma concentrations of ketoconazole were high and persisted longer than expected in Greyhounds.
Conclusions and Clinical Relevance—Ketoconazole had no significant effect on morphine pharmacokinetics, and the pharmacodynamics were similar between treatment groups. Plasma concentrations of ketoconazole were higher than expected and persisted longer than expected in Greyhounds.
Objective—To determine the pharmacokinetics of tramadol, the active metabolite O-desmethyltrcamadol, and the metabolites N-desmethyltramadol and N,O-didesmethyltramadol after oral tramadol administration and to determine the antinociceptive effects of the drug in Greyhounds.
Animals—6 healthy 2- to 3-year-old Greyhounds (3 male and 3 female), weighing 25.5 to 41.1 kg.
Procedures—A mean dose of 9.9 mg of tramadol HCl/kg was administered PO as whole tablets. Blood samples were obtained prior to and at various points after administration to measure plasma concentrations of tramadol and its metabolites via liquid chromatography with mass spectrometry. Antinociceptive effects were determined by measurement of pain-pressure thresholds with a von Frey device.
Results—Tramadol was well tolerated, and a significant increase in pain-pressure thresholds was evident 5 and 6 hours after administration. The mean maximum plasma concentrations of tramadol, O-desmethyltramadol, N-desmethyltramadol, and N,O-didesmethyltramadol were 215.7, 5.7, 379.1, and 2372 ng/mL, respectively. The mean area-under-the-curve values for the compounds were 592, 16, 1,536, and 1,013 h·ng/mL, respectively. The terminal half-lives of the compounds were 1.1, 1.4, 2.3, and 3.6 hours, respectively. Tramadol was detected in urine 5 days, but not 7 days, after administration.
Conclusions and Clinical Relevance—Oral tramadol administration yielded antinociceptive effects in Greyhounds, but plasma concentrations of tramadol and O-desmethyltramadol were lower than expected. Compared with the approved dose (100 mg, PO) in humans, a mean dose of 9.9 mg/kg, PO resulted in similar tramadol but lower O-desmethyltramadol plasma concentrations in Greyhounds.
Objective—To determine pharmacokinetics, efficacy, and adverse effects of topically administered selamectin in flea-infested rabbits.
Animals—18 healthy 5-month-old New Zealand White rabbits.
Procedures—On day 0, rabbits (n = 6/group) received topically applied selamectin at doses of 10 or 20 mg/kg or received no treatment. Each rabbit was infested with 50 fleas (Ctenocephalides felis) on days −1, 7, and 14. Live and dead flea counts were performed on days 2, 9, and 16, and treatment efficacy was calculated. Blood samples were collected prior to drug administration and at 6 and 12 hours and 1, 2, 3, 5, 7, 10, 14, 21, and 28 days after treatment for determination of plasma selamectin concentrations via high-performance liquid chromatography with mass spectrometry. Pharmacokinetic parameters were determined.
Results—On day 2, efficacy of selamectin against flea populations of rabbits in the 10 and 20 mg/kg treatment groups was 91.3% and 97.1%, respectively, but by day 9, these values decreased to 37.7% and 74.2%, respectively. Mean terminal half-life and maximum plasma concentrations of selamectin were 0.93 days and 91.7 ng/mL, respectively, for rabbits in the 10 mg/kg group and 0.97 days and 304.2 ng/mL, respectively, for rabbits in the 20 mg/kg group. No adverse effects were detected.
Conclusions and Clinical Relevance—Selamectin was rapidly absorbed transdermally and was rapidly eliminated in rabbits. Results suggested that topical administration at a dosage of 20 mg/kg every 7 days is efficacious for treatment of flea infestation in rabbits. Further studies are needed to assess long-term safety in rabbits following repeated applications.
To determine plasma tramadol concentrations in cats following a single dose of oral and transdermal formulations and the pharmacokinetics for and the concentration of tramadol in the transdermal formulation.
8 healthy client-owned domestic shorthair cats.
1 cat was orally administered 1 dose of tramadol (2 mg/kg), and 7 cats received 1 dose of a proprietary compounded tramadol gel product (median actual dose, 2.8 mg/kg) applied to their inner pinnae. Plasma tramadol concentrations were measured with high-performance liquid chromatography–mass spectrometry at fixed times over 24 hours.
Plasma tramadol concentrations were undetectable or much lower (range, < 1 to 4.3 ng/mL) following application of the transdermal formulation, compared with those following oral administration (maximum plasma tramadol concentration, 261.3 ng/mL [at 4 hours]). Tramadol pharmacokinetics for the transdermal formulation could not be determined. Tramadol concentrations of the transdermal gel product exceeded the estimated label dose in all analyzed gel samples, with concentrations greater than the 90% to 110% United States Pharmacopeia standard for compounded drugs.
CONCLUSIONS AND CLINICAL RELEVANCE
Application of 1 dose of the proprietary transdermal formulation did not yield clinically relevant plasma tramadol concentrations in cats. Although this proprietary formulation is currently available to prescribing veterinarians, it should be used with caution.
OBJECTIVE To determine pharmacokinetics of butorphanol delivered via osmotic pumps in common peafowl (Pavo cristatus) as a method for analgesic administration to avian species.
ANIMALS 14 healthy adult male common peafowl.
PROCEDURES A preliminary experiment was conducted with 2 birds to establish time point and concentration requirements. Then, the remaining 12 birds were anesthetized, and 2 osmotic pumps containing butorphanol (volume, 2 mL; mean dosage, 247 μg/kg/h) were implanted subcutaneously in each bird for 7 days prior to removal. Blood samples were collected before pump implantation (time 0); 3, 6, 12, 24, 48, 72, 96, 120, 144, and 168 hours after pump implantation; and 3 and 6 hours after pump removal. Plasma butorphanol concentrations were measured via liquid chromatography–mass spectrometry.
RESULTS Plasma concentrations peaked (mean, 106.4 μg/L; range, 61.8 to 133.0 μg/L) at a mean of 39.0 hours, with no evidence of sedation in any bird. After pump removal, butorphanol was rapidly eliminated (half-life, 1.45 hours; range, 1.31 to 1.64 hours; n = 5). Mean clearance per fraction of dose absorbed was 2.89 L/kg/h (range, 2.00 to 5.55 L/kg/h). Mean amount of time the plasma butorphanol concentration was ≥ 60 μg/L was 85.6 hours (range, 3.5 to 155.3 hours).
CONCLUSIONS AND CLINICAL RELEVANCE Plasma concentrations of butorphanol in common peafowl were maintained at or above reported efficacious analgesic concentrations. This study established a method for administering analgesics to avian patients without the need for frequent handling or injections. Use of these osmotic pumps may provide options for avian analgesia.
To determine the effects of coadministration of naltrexone, a human opioid abuse deterrent, on the pharmacokinetics and pharmacodynamics of a methadone-fluconazole combination administered orally to dogs.
12 healthy Beagles.
Dogs (body weight, 10.7 to 13.9 kg) were randomly allocated to 2 groups in a parallel design study. All dogs received fluconazole (100 mg [7.19 to 9.35 mg/kg], PO). Twelve hours later (time 0), dogs were administered methadone (10 mg [0.72 to 0.93 mg/kg]) plus fluconazole (50 mg [3.62 to 4.22 mg/kg]; methadone-fluconazole) or methadone (10 mg [0.72 to 0.93 mg/kg]) plus fluconazole (50 mg [3.60 to 4.67 mg/kg]) and naltrexone (2.5 mg [0.18 to 0.23 mg/kg]; methadone-fluconazole-naltrexone), PO, in a gelatin capsule. Blood samples were collected for pharmacokinetic analysis, and rectal temperature and sedation were assessed to evaluate opioid effects at predetermined times up to 24 hours after treatment.
Most dogs had slight sedation during the 12 hours after drug administration; 1 dog/group had moderate sedation at 1 time point. Mean rectal temperatures decreased significantly from baseline (immediate pretreatment) values from 2 to ≥ 12 hours and 2 to ≥ 8 hours after methadone-fluconazole and methadone-fluconazole-naltrexone treatment, respectively. Geometric mean maximum observed concentration of methadone in plasma was 35.1 and 33.5 ng/mL and geometric mean terminal half-life was 7.92 and 7.09 hours after methadone-fluconazole and methadone-fluconazole-naltrexone treatment, respectively. Naltrexone was sporadically detected in 1 dog. The active naltrexone metabolite, β-naltrexol, was not detected. The inactive metabolite, naltrexone glucuronide, was detected in all dogs administered methadone-fluconazole-naltrexone.
CONCLUSIONS AND CLINICAL RELEVANCE
Opioid effects were detected after oral administration of methadone-fluconazole or methadone-fluconazole-naltrexone. Further studies assessing additional opioid effects, including antinociception, are needed.
Objective—To assess pharmacokinetic and pharmacodynamic properties of dexamethasone administered PO as a solution or powder, compared with properties of dexamethasone solution administered IV, in apparently healthy horses.
Animals—6 adult horses.
Procedures—Serum cortisol concentration for each horse was determined before each treatment (baseline values). Dexamethasone (0.05 mg/kg) was administered PO (in solution or powdered form) or IV (solution) to horses from which feed had or had not been withheld (unfed and fed horses, respectively). Each horse received all 6 treatments in random order at 2-week intervals; PO and IV administrations of dexamethasone were accompanied by IV or PO sham treatments, respectively. Plasma dexamethasone and serum cortisol concentrations were assessed at predetermined intervals.
Results—Maximum plasma dexamethasone concentration after PO administration of powdered dexamethasone in unfed horses was significantly higher than the maximum plasma concentration after PO administration of dexamethasone solution in unfed or fed horses. Mean bioavailability of dexamethasone ranged from 28% to 66% but was not significantly different among horses receiving either formulation PO in the unfed or fed state. After dexamethasone treatment PO or IV, serum cortisol concentrations were significantly less than baseline at 1 to 72 hours in unfed horses and at 2 to 48 hours in fed horses.
Conclusions and Clinical Relevance—PO or IV administration of dexamethasone resulted in suppression of cortisol secretion in unfed and fed adult horses; the magnitude of suppression did not differ among treatment groups, and serum cortisol concentrations returned to baseline after 48 to 72 hours.
Procedures—Meloxicam (0.5 mg/kg, IV, or 1.0 mg/kg, PO) was administered in a randomized crossover design with a 10-day washout period. Blood samples were collected at predetermined times over 96 hours. Serum drug concentrations were determined by high-pressure liquid chromatography with mass spectrometry. Computer software was used to estimate values of pharmacokinetic parameters through noncompartmental methods.
Results—Following IV administration (n = 5), the geometric mean (range) elimination half-life was 14.0 hours (10.5 to 17.0 hours), volume of distribution was 0.204 L/kg (0.171 to 0.272 L/kg), and clearance was 0.17 mL/min/kg (0.12 to 0.27 mL/min/kg). Following oral administration (n = 6), maximum serum concentration was 1.72 μg/mL (1.45 to 1.93 μg/mL), time to maximum serum concentration was 19.0 hours (12.0 to 24.0 hours), clearance per bioavailability was 0.22 mL/min/kg (0.16 to 0.30 mL/min/kg), and terminal half-life was 15.4 hours (13.2 to 17.7 hours). Bioavailability of orally administered meloxicam was calculated as 72% (40% to 125%; n = 5). No adverse effects were evident following meloxicam administration via either route.
Conclusions and Clinical Relevance—Meloxicam administered PO at 1.0 mg/kg has good bioavailability with slow elimination kinetics in sheep. These data suggested that meloxicam may be clinically useful, provided the safety and analgesic efficacy of meloxicam as well as feed-related influences on its pharmacokinetics are established in ruminants.
Objective—To determine the pharmacokinetics of meloxicam (1 mg/kg) in rabbits after oral administration of single and multiple doses.
Animals—6 healthy rabbits.
Procedures—A single dose of meloxicam (1 mg/kg, PO) was administered to the rabbits. After a 10-day washout period, meloxicam (1 mg/kg, PO) was administered to rabbits every 24 hours for 5 days. Blood samples were obtained from rabbits at predetermined intervals during both treatment periods. Plasma meloxicam concentrations were determined, and noncompartmental pharmacokinetic analysis was performed.
Results—The mean peak plasma concentration and area under the plasma concentration-versus-time curve extrapolated to infinity after administration of a single dose of meloxicam were 0.83 μg/mL and 10.37 h•μg/mL, respectively. After administration of meloxicam for 5 days, the mean peak plasma concentration was 1.33 μg/mL, and the area under the plasma concentration-versus-time curve from the time of administration of the last dose to 24 hours after that time was 18.79 h•μg/mL. For single- and multiple-dose meloxicam experiments, the mean time to maximum plasma concentration was 6.5 and 5.8 hours and the mean terminal half-life was 6.1 and 6.7 hours, respectively.
Conclusions and Clinical Relevance—Plasma concentrations of meloxicam for rabbits in the present study were proportionally higher than those previously reported for rabbits receiving 0.2 mg of meloxicam/kg and were similar to those determined for animals of other species that received clinically effective doses. A dose of 1 mg/kg may be necessary to achieve clinically effective circulating concentrations of meloxicam in rabbits, although further studies are needed.
PROCEDURES Enrofloxacin (20 mg/kg) was administered SC once to 6 prairie dogs and IV once to 2 prairie dogs. A blood sample was collected from each animal immediately before (0 hours) and 0.5, 1, 2, 4, 8, 12, and 24 hours after drug administration to evaluate the pharmacokinetics of enrofloxacin and ciprofloxacin. Plasma enrofloxacin and ciprofloxacin concentrations were quantified with ultraperformance liquid chromatography–mass spectrometry, and noncompartmental pharmacokinetic analysis was performed.
RESULTS Enrofloxacin was biotransformed to ciprofloxacin in the prairie dogs used in the study. For total fluoroquinolones (enrofloxacin and ciprofloxacin), the mean (range) of peak plasma concentration, time to maximum plasma concentration, and terminal half-life after SC administration were 4.90 μg/mL (3.44 to 6.08 μg/mL), 1.59 hours (0.5 to 2.00 hours), and 4.63 hours (4.02 to 5.20 hours), respectively.
CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that administration of enrofloxacin (20 mg/kg, SC, q 24 h) in black-tailed prairie dogs may be appropriate for treatment of infections with bacteria for which the minimum inhibitory concentration of enrofloxacin is ≤ 0.5 μg/mL. However, clinical studies are needed to determine efficacy of such enrofloxacin treatment.