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Abstract

OBJECTIVE

To characterize the pharmacokinetics of mycophenolate mofetil (MMF) following single-dose IV or PO administration, characterize the pharmacokinetics of MMF following long-term PO administration, and describe the clinicopathologic effects of long-term MMF administration in horses.

ANIMALS

12 healthy adult horses.

PROCEDURES

In phase 1, 6 horses received a single IV (2.5 mg/kg) or PO (5 mg/kg) dose of MMF in a randomized balanced crossover assessment (≥ 2-week interval between administrations). In phase 2, 6 other horses received MMF for 60 days (5 mg/kg, PO, q 24 h for 30 days and then 5 mg/kg, PO, q 48 h for an additional 30 days).

RESULTS

Following IV (single-dose) or PO (single- or multiple-dose) administration, MMF was rapidly converted to mycophenolic acid. For single-dose PO administration, mean ± SD maximum plasma mycophenolic acid concentration was 1,778.3 ± 441.5 ng/mL at 0.71 ± 0.29 hours. For single-dose IV administration, mean systemic clearance and volume of distribution at steady state were 0.689 ± 0.194 L/h/kg and 1.57 ± 0.626 L/kg, respectively. Following single doses, mean terminal half-life was 3.99 ± 0.865 hours for IV administration and 4.02 ± 1.01 hours for PO administration. The accumulation index following long-term PO administration was 1.0 ± 0.002, and the terminal half-life was 4.59 ± 1.25 hours following the final dose on day 60. None of the horses developed abnormal clinical signs or had any consistently abnormal clinicopathologic findings.

CONCLUSIONS AND CLINICAL RELEVANCE

Further investigation of the clinical efficacy of long-term MMF treatment of horses with autoimmune diseases is warranted.

Full access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To determine the safety and pharmacokinetics of various doses of plant-derived cannabidiol (CBD) versus placebo following repeated oral administration.

ANIMALS

20 healthy adult Beagles.

PROCEDURES

In a randomized, blinded, placebo-controlled trial, dogs were randomized to 5 groups balanced in body weight and sex (n = 4 dogs/group) and received a CBD (1, 2, 4, or 12 mg/kg; from cannabis extract) or placebo oil formulation PO once daily for 28 days. Outcome variables were assessed through daily health observations, veterinary examinations, CBC, and serum biochemical analysis. Blood samples were collected at various time points to estimate 24-hour pharmacokinetic profiles of CBD and selected metabolites (7-carboxy-CBD and 7-hydroxy-CBD).

RESULTS

Repeated CBD administration was well tolerated by dogs, with no clinically important changes in measured safety outcomes. Veterinary examinations revealed no clinically important abnormal findings. Adverse events were mild in severity. Relative to placebo administration, CBD administration at 12 mg/kg/d resulted in more gastrointestinal adverse events (mainly hypersalivation) and significantly higher serum alkaline phosphatase activity. Total systemic exposure to CBD increased on a dose-dependent basis following both acute (first dose) and chronic (28 days) administration. Within each CBD dose group, repeated administration increased total systemic exposure to CBD 1.6- to 3.3-fold. The 24-hour trough plasma CBD concentrations were also dose dependent, with a steady state reached following 2 weeks of administration.

CONCLUSIONS AND CLINICAL RELEVANCE

Repeated, daily oral administration of the CBD formulation led to dose-dependent increases in total systemic exposure to CBD and 24-hour trough plasma concentrations in healthy dogs. These findings could help guide dose selection.

Full access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To evaluate the pharmacokinetics of hydromorphone hydrochloride after IM and IV administration to orange-winged Amazon parrots (Amazona amazonica).

ANIMALS

8 orange-winged Amazon parrots (4 males and 4 females).

PROCEDURES

Hydromorphone (1 mg/kg) was administered once IM. Blood samples were collected 5 minutes and 0.5, 1.5, 2, 3, 6, and 9 hours after drug administration. Plasma hydromorphone concentrations were determined with liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were calculated with a compartmental model. The experiment was repeated 1 month later with the same dose of hydromorphone administered IV.

RESULTS

Plasma hydromorphone concentrations were > 1 ng/mL for 6 hours in 8 of 8 and 6 of 7 parrots after IM and IV injection, respectively. After IM administration, mean bioavailability was 97.6%, and mean maximum plasma concentration was 179.1 ng/mL 17 minutes after injection. Mean volume of distribution and plasma drug clearance were 4.24 L/kg and 64.2 mL/min/kg, respectively, after IV administration. Mean elimination half-lives were 1.74 and 1.45 hours after IM and IV administration, respectively.

CONCLUSIONS AND CLINICAL RELEVANCE

Hydromorphone hydrochloride had high bioavailability and rapid elimination after IM administration, with rapid plasma clearance and a large volume of distribution after IV administration in orange-winged Amazon parrots. Drug elimination half-lives were short. Further pharmacokinetic studies of hydromorphone and its metabolites, including investigation of multiple doses, different routes of administration, and sustained-release formulations, are recommended.

Restricted access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To determine the pharmacokinetics and efficacy of trazodone following rectal administration of a single dose to healthy dogs.

ANIMALS

6 healthy adult dogs.

PROCEDURES

Each dog received a single dose of trazodone (approx 8 mg/kg) per rectum. Trazodone tablets were crushed into a powder, mixed with 5 mL of tap water, and injected into the rectum via a red rubber catheter. Sedation scores were assigned, and blood samples were collected for determination of plasma trazodone concentration at predetermined times before and after drug administration. Pharmacokinetic parameters were estimated by noncompartmental analysis.

RESULTS

Plasma trazodone concentration remained below the detection limit for 1 dog even though it became moderately sedate. Median (interquartile [25th to 75th percentile] range [IQR]) maximum plasma trazodone concentration and volume of distribution and clearance corrected for bioavailability were 1.00 μg/mL (0.66 to 1.40 μg/mL), 10.3 L/kg (7.37 to 14.4 L/kg), and 639 mL/kg/h (594 to 719 mL/kg/h), respectively. Median time to maximum plasma trazodone concentration and elimination half-life were 15 minutes (range, 15 to 30 minutes) and 12 hours (IQR, 7.99 to 12.7 hours), respectively. All dogs became mildly or moderately sedate, and the extent of sedation was maximal at a median of 30 minutes (IQR, 30 to 60 minutes) after trazodone administration. No adverse effects were observed.

CONCLUSIONS AND CLINICAL RELEVANCE

Rectal administration of trazodone may be a viable option for sedation and treatment of anxiety in dogs for which administration of sedatives and anxiolytics by other routes is contraindicated. Further research is necessary to better elucidate the pharmacokinetics and efficacy of trazodone following rectal administration and determine optimal dosing.

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in American Journal of Veterinary Research

Abstract

OBJECTIVE

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.

ANIMALS

12 healthy Beagles.

PROCEDURES

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.

RESULTS

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.

Restricted access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To determine the pharmacokinetics of amantadine after oral administration of single and multiple doses to orange-winged Amazon parrots (Amazona amazonica).

ANIMALS

12 adult orange-winged Amazon parrots (6 males and 6 females).

PROCEDURES

A single dose of amantadine was orally administered to 6 birds at 5 mg/kg (n = 2), 10 mg/kg (2), and 20 mg/kg (2) in a preliminary trial. On the basis of the results, a single dose of amantadine (10 mg/kg, PO) was administered to 6 other birds. Two months later, multiple doses of amantadine (5 mg/kg, PO, q 24 h for 7 days) were administered to 8 birds. Heart rate, respiratory rate, behavior, and urofeces were monitored. Plasma concentrations of amantadine were measured via tandem liquid chromatography–mass spectrometry. Pharmacokinetic parameter estimates were determined via noncompartmental analysis.

RESULTS

Mean ± SD maximum plasma concentration, time to maximum plasma concentration, half-life, and area under the concentration-versus-time curve from the last dose to infinity were 1,174 ± 186 ng/mL, 3.8 ± 1.8 hours, 23.2 ± 2.9 hours, and 38.6 ± 7.4 μg·h/mL, respectively, after a single dose and 1,185 ± 270 ng/mL, 3.0 ± 2.4 hours, 21.5 ± 5.3 hours, and 26.3 ± 5.7 μg·h/mL, respectively, at steady state after multiple doses. No adverse effects were observed.

CONCLUSIONS AND CLINICAL RELEVANCE

Once-daily oral administration of amantadine at 5 mg/kg to orange-winged Amazon parrots maintained plasma concentrations above those considered to be therapeutic in dogs. Further studies evaluating safety and efficacy of amantadine in orange-winged Amazon parrots are warranted.

Restricted access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To compare analgesic efficacy and fetal effects between transdermal administration of fentanyl and IM administration of buprenorphine in pregnant sheep.

ANIMALS

12 healthy pregnant ewes.

PROCEDURES

Before study initiation, each ewe was confirmed pregnant with a single fetus between 113 and 117 days of gestation. Ewes were randomly assigned to receive buprenorphine (0.01 mg/kg, IM, q 8 h for 48 hours beginning 1 hour before anesthesia induction; n = 6) or fentanyl (a combination of transdermal fentanyl patches sufficient to deliver a dose of 2 μg of fentanyl/kg/h applied between the dorsal borders of the scapulae 24 hours before anesthesia induction; 6). Ewes were anesthetized and underwent a surgical procedure to instrument the fetus with an arterial catheter and place a catheter in utero for collection of amniotic fluid samples. Physiologic variables and behavioral changes indicative of pain were assessed, and amniotic fluid and blood samples from ewes and fetuses were collected for determination of drug concentrations at predetermined times.

RESULTS

Both protocols provided acceptable postoperative analgesia with no adverse effects observed in the ewes or fetuses. Compared with the buprenorphine protocol, the fentanyl protocol induced more profound analgesia, decreased the requirement for isoflurane during surgery, and was associated with a shorter anesthesia recovery time. Fetal indices did not differ significantly between the 2 analgesic protocols.

CONCLUSIONS AND CLINICAL RELEVANCE

Results indicated that both protocols provided acceptable analgesia. However, the fentanyl protocol was superior in regard to the extent of analgesia induced, inhalant-sparing effects, and anesthesia recovery time.

Restricted access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To determine the pharmacokinetics of hydromorphone hydrochloride after IV and IM administration in guinea pigs (Cavia porcellus).

ANIMALS

8 healthy adult guinea pigs (4 sexually intact females and 4 sexually intact males).

PROCEDURES

In a crossover study, hydromorphone (0.3 mg/kg) was administered once IM (epaxial musculature) or IV (cephalic catheter) to each guinea pig at a 1-week interval (2 treatments/guinea pig). Blood samples were collected before and at predetermined intervals after drug administration via a vascular access port. Plasma hydromorphone concentrations were determined by liquid chromatography–tandem mass spectrometry. Noncompartmental analysis of data was used to calculate pharmacokinetic parameters.

RESULTS

Mean ± SD clearance and volume of distribution for hydromorphone administered IV were 52.8 ± 13.5 mL/min/kg and 2.39 ± 0.479 L/kg, respectively. Mean residence time determined for the IV and IM administration routes was 0.77 ± 0.14 hours and 0.99 ± 0.34 hours, respectively. The maximum observed plasma concentration following IM administration of hydromorphone was 171.9 ± 29.4 ng/mL. No sedative effects were observed after drug administration by either route.

CONCLUSIONS AND CLINICAL RELEVANCE

Pharmacokinetic data indicated that hydromorphone at a dose of 0.3 mg/kg may be administered IV every 2 to 3 hours or IM every 4 to 5 hours to maintain a target plasma concentration between 2 and 4 ng/mL in guinea pigs. Hydromorphone had high bioavailability after IM administration. Further research is necessary to evaluate the effects of other doses and administration routes and the analgesic effects of hydromorphone in guinea pigs.

Restricted access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To characterize the pharmacokinetics of a clinically relevant dose of misoprostol administered PO or per rectum (PR) to horses.

ANIMALS

8 healthy adult horses.

PROCEDURES

In a randomized 3-way crossover design, horses received a single dose of misoprostol (5 μg/kg) administered PO (with horses fed and unfed) and PR, with a minimum 3-week washout period separating the experimental conditions. Blood samples were obtained before and at various points after drug administration (total, 24 hours), and plasma concentrations of misoprostol free acid were measured.

RESULTS

Mean maximum plasma concentration of misoprostol was significantly higher in the PR condition (mean ± SD, 967 ± 492 pg/mL) and unfed PO condition (655 ± 259 pg/mL) than in the fed PO condition (352 ± 109 pg/mL). Mean area under the concentration-versus-time curve was significantly lower in the PR condition (219 ± 131 pg•h/mL) than in the unfed (1,072 ± 360 pg•h/mL) and fed (518 ± 301 pg•h/mL) PO conditions. Mean time to maximum concentration was ≤ 30 minutes for all conditions. Mean disappearance half-life was shortest in the PR condition (21 ± 29 minutes), compared with values for the unfed (170 ± 129 minutes) and fed (119 ± 51 minutes) PO conditions. No adverse effects were noted.

CONCLUSIONS AND CLINICAL RELEVANCE

Misoprostol was rapidly absorbed and eliminated regardless of whether administered PO or PR to horses. Rectal administration may be a viable alternative for horses that cannot receive misoprostol PO, but this route may require more frequent administration to maintain therapeutic drug concentrations.

Restricted access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To determine pharmacokinetic and pharmacodynamic properties of the injectable formulation of dexmedetomidine administered via the oral transmucosal (OTM) route to healthy dogs.

ANIMALS

6 healthy dogs.

PROCEDURES

Injectable dexmedetomidine was administered IV (5 μg/kg) or via the OTM route (20 μg/kg) in a blinded, single-observer, randomized crossover study. Dogs received dexmedetomidine and a sham treatment at each administration. Serial blood samples were collected from a catheter in a saphenous vein. Heart rate, respiratory rate, and subjective sedation score were assessed for 24 hours after administration. Plasma samples were analyzed for dexmedetomidine concentrations by use of ultraperformance liquid chromatography–tandem mass spectrometry.

RESULTS

For the OTM route, the mean ± SD maximum plasma concentration was 3.8 ± 1.3 ng/mL, which was detected 73 ± 33 minutes after administration. The mean maximum concentration for the IV dose, when extrapolated to the time of administration, was 18.6 ± 3.3 ng/mL. The mean terminal-phase half-life was 152 ± 146 minutes and 36 ± 6 minutes for OTM and IV administration, respectively. After IV administration, total clearance was 8.0 ± 1.6 mL/min/kg and volume of distribution at steady state was 371 ± 72 mL/kg. Bioavailability for OTM administration of dexmedetomidine was 11.2 ± 4.5%. Peak sedation scores did not differ significantly between routes of administration. Decreases in heart rate, respiratory rate, and peak sedation score were evident sooner after IV administration.

CONCLUSIONS AND CLINICAL RELEVANCE

OTM administration of the injectable formulation of dexmedetomidine resulted in a similar degree of sedation and prolonged duration of action, compared with results for IV administration, despite relatively low bioavailability.

Restricted access
in American Journal of Veterinary Research