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 evaluate the correlation between halftime
of liquid-phase gastric emptying (T50), determined
with nuclear scintigraphy using technetium
Tc 99m pentetate, and absorption variables of orally
Animals—6 mature horses.
Procedure—Technetium Tc 99m pentetate (10 mCi)
and acetaminophen (20 mg/kg of body weight) were
administered simultaneously in 200 ml of water. Serial
left and right lateral images of the stomach region
were obtained with a gamma camera, and T50 determined
separately for counts obtained from the left
side, the right side and the geometric mean. Power
exponential curves were used for estimation of T50
and modified R2 values for estimation of goodness of
fit of the data. Serial serum samples were taken, and
acetaminophen concentration was determined, using
fluorescence polarization immunoassay. Maximum
serum concentration (Cmax), time to reach maximum
serum concentration (Tmax), area under the curve for
240 minutes and the absorption constant (Ka) were
determined, using a parameter estimation program.
Correlations were calculated, using the Spearman
rank correlation coefficient.
Results—Correlations between T50 and Tmax and
between T50 and Ka were significant.
Conclusions and Clinical Relevance—Tmax and Ka
are valuable variables in the assessment of liquidphase
gastric emptying using acetaminophen absorption.
Acetaminophen absorption may be a valuable
alternative to nuclear scintigraphy in the determination
of gastric emptying rates in equine patients with
normally functioning small intestine. (Am J Vet Res
To compare pharmacokinetics of levetiracetam in serum and CSF of cats after oral administration of extended-release (ER) levetiracetam.
9 healthy cats.
Cats received 1 dose of a commercially available ER levetiracetam product (500 mg, PO). Thirteen blood and 10 CSF samples were collected over a 24-hour period for pharmacokinetic analysis. After 1 week, cats received 1 dose of a compounded ER levetiracetam formulation (500 mg, PO), and samples were obtained at the same times for analysis.
CSF concentrations of levetiracetam closely paralleled serum concentrations. There were significant differences between the commercially available product and the compounded formulation for mean ± SD serum maximum concentration (Cmax; 126 ± 33 μg/mL and 169 ± 51 μg/mL, respectively), Cmax corrected for dose (0.83 ± 0.10 μg/mL/mg and 1.10 ± 0.28 μg/mL/mg, respectively), and time to Cmax (5.1 ± 1.6 hours and 3.1 ± 1.5 hours, respectively). Half-life for the commercially available product and compounded formulation of ER levetiracetam was 4.3 ± 2.0 hours and 5.0 ± 1.6 hours, respectively.
CONCLUSIONS AND CLINICAL RELEVANCE
The commercially available product and compounded formulation of ER levetiracetam both maintained concentrations in healthy cats 12 hours after oral administration that have been found to be therapeutic in humans (ie, 5 μg/mL). Results of this study supported dosing intervals of 12 hours, and potentially 24 hours, for oral administration of ER levetiracetam to cats. Monitoring of serum concentrations of levetiracetam can be used as an accurate representation of levetiracetam concentrations in CSF of cats.
To characterize the pharmacokinetics of a clinically relevant dose of misoprostol administered PO or per rectum (PR) to horses.
8 healthy adult horses.
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.
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.
Objective—To assess pharmacokinetics, efficacy, and tolerability of oral levetiracetam administered as an adjunct to phenobarbital treatment in cats with poorly controlled suspected idiopathic epilepsy.
Design—Open-label, noncomparative clinical trial.
Animals—12 cats suspected to have idiopathic epilepsy that was poorly controlled with phenobarbital or that had unacceptable adverse effects when treated with phenobarbital.
Procedures—Cats were treated with levetiracetam (20 mg/kg [9.1 mg/lb], PO, q 8 h). After a minimum of 1 week of treatment, serum levetiracetam concentrations were measured before and 2, 4, and 6 hours after drug administration, and maximum and minimum serum concentrations and elimination half-life were calculated. Seizure frequencies before and after initiation of levetiracetam treatment were compared, and adverse effects were recorded.
Results—Median maximum serum levetiracetam concentration was 25.5 μg/mL, median minimum serum levetiracetam concentration was 8.3 μg/mL, and median elimination half-life was 2.9 hours. Median seizure frequency prior to treatment with levetiracetam (2.1 seizures/mo) was significantly higher than median seizure frequency after initiation of levetiracetam treatment (0.42 seizures/mo), and 7 of 10 cats were classified as having responded to levetiracetam treatment (ie, reduction in seizure frequency of ≥ 50%). Two cats had transient lethargy and inappetence.
Conclusions and Clinical Relevance—Results suggested that levetiracetam is well tolerated in cats and may be useful as an adjunct to phenobarbital treatment in cats with idiopathic epilepsy.
Objective—To determine the pharmacokinetics of
carvedilol administered IV and orally and determine
the dose of carvedilol required to maintain plasma
concentrations associated with anticipated therapeutic
efficacy when administered orally to dogs.
Animals—8 healthy dogs.
Procedures—Blood samples were collected for 24
hours after single doses of carvedilol were administered
IV (175 µg/kg) or PO (1.5 mg/kg) by use of a
crossover nonrandomized design. Carvedilol concentrations
were detected in plasma by use of high-performance
liquid chromatography. Plasma drug concentration
versus time curves were subjected to noncompartmental
Results—The median peak concentration (extrapolated)
of carvedilol after IV administration was
476 ng/mL (range, 203 to 1,920 ng/mL), elimination
half-life (t1/2) was 282 minutes (range, 19 to 1,021
minutes), and mean residence time (MRT) was 360
minutes (range, 19 to 819 minutes). Volume of distribution
at steady state was 2.0 L/kg (range, 0.7 to 4.3
L/kg). After oral administration of carvedilol, the median
peak concentration was 24 µg/mL (range, 9 to
173 µg/mL), time to maximum concentration was 90
minutes (range, 60 to 180 minutes), t1/2 was 82 minutes
(range, 64 to 138 minutes), and MRT was 182
minutes (range, 112 to 254 minutes). Median bioavailability
after oral administration of carvedilol was 2.1%
(range, 0.4% to 54%).
Conclusions and Clinical Relevance—Although
results suggested a 3-hour dosing interval on the
basis of MRT, pharmacodynamic studies investigating
the duration of β-adrenoreceptor blockade provide a
more accurate basis for determining the dosing interval
of carvedilol. (Am J Vet Res 2005;66:2172–2176)
OBJECTIVE To evaluate the pharmacokinetics of zonisamide following rectal administration of 20 or 30 mg/kg suspended in sterile water or polyethylene glycol (PEG) to healthy dogs and determine whether either dose resulted in plasma zonisamide concentrations within the recommended therapeutic target range (10 to 40 μg/mL).
ANIMALS 8 healthy mixed-breed dogs.
PROCEDURES Each dog received each of 2 doses (20 or 30 mg/kg) of zonisamide suspended in each of 2 delivery substrates (sterile water or PEG) in a randomized crossover study with a 7-day washout period between phases. A blood sample was collected from each dog immediately before and at predetermined times for 48 hours after zonisamide administration. Plasma zonisamide concentrations were determined by high-performance liquid chromatography, and data were analyzed with a noncompartmental model.
RESULTS Mean maximum plasma concentration, time to maximum plasma concentration, mean residence time, and elimination half-life did not differ significantly among the 4 treatments. The mean maximum plasma concentration for all 4 treatments was less than the therapeutic target range. The mean ± SD area under the concentration-time curve for the 30 mg/kg-in-water treatment (391.94 ± 237.00 h•μg/mL) was significantly greater than that for the 20 mg/kg-in-water (146.19 ± 66.27 h•μg/mL) and 20 mg/kg-in-PEG (87.09 ± 96.87 h•μg/mL) treatments.
CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that rectal administration of zonisamide at doses of 20 and 30 mg/kg failed to achieve plasma zonisamide concentrations within the recommended therapeutic target range. Therefore, rectal administration of zonisamide cannot be recommended as a suitable alternative to oral administration.
OBJECTIVE To determine pharmacokinetics after oral administration of single and multiple doses and to assess the safety of zonisamide in Hispaniolan Amazon parrots (Amazona ventralis).
ANIMALS 12 adult Hispaniolan Amazon parrots.
PROCEDURES Zonisamide (30 mg/kg, PO) was administered once to 6 parrots in a single-dose trial. Six months later, a multiple-dose trial was performed in which 8 parrots received zonisamide (20 mg/kg, PO, q 12 h for 10 days) and 4 parrots served as control birds. Safety was assessed through monitoring of body weight, attitude, and urofeces and comparison of those variables and results of CBC and biochemical analyses between control and treatment groups.
RESULTS Mean ± SD maximum plasma concentration of zonisamide for the single- and multiple-dose trials was 21.19 ± 3.42 μg/mL at 4.75 hours and 25.11 ± 1.81 μg/mL at 2.25 hours after administration, respectively. Mean plasma elimination half-life for the single- and multiple-dose trials was 13.34 ± 2.10 hours and 9.76 ± 0.93 hours, respectively. Pharmacokinetic values supported accumulation in the multiple-dose trial. There were no significant differences in body weight, appearance of urofeces, or appetite between treated and control birds. Although treated birds had several significant differences in hematologic and biochemical variables, all variables remained within reference values for this species.
CONCLUSIONS AND CLINICAL RELEVANCE Twice-daily oral administration of zonisamide to Hispaniolan Amazon parrots resulted in plasma concentrations known to be therapeutic in dogs without evidence of adverse effects on body weight, attitude, and urofeces or clinically relevant changes to hematologic and biochemical variables.
To describe misoprostol pharmacokinetics and anti-inflammatory efficacy when administered orally or per rectum in endotoxin-challenged horses.
6 healthy geldings.
A randomized 3-treatment crossover design was performed with a minimum washout period of 28 days between treatment arms. Prior to endotoxin challenge (lipopolysaccharide, 30 ng/kg IV over 30 minutes), horses received misoprostol (5 µg/kg once) per os (M-PO) or per rectum (M-PR) or water as control (CON). Clinical parameters were evaluated and blood samples obtained to measure plasma misoprostol free acid concentration, leukocyte counts, and tumor necrosis factor-α (TNFα) and interleukin 6 (IL-6) leukocyte gene expression and serum concentrations.
In the M-PO treatment arm, maximum plasma concentration and area under the concentration-versus-time curve (mean ± SD) were higher (5,209 ± 3,487 pg/mL and 17,998,254 ± 13,194,420 h·pg/mL, respectively) and median (interquartile range) time to maximum concentration (25 min [18 to 34 min]) was longer than in the M-PR treatment arm (854 ± 855 pg/mL; 644,960 ± 558,866 h·pg/mL; 3 min [3 to 3.5 min]). Significant differences in clinical parameters, leukocyte counts, and TNFα or IL-6 gene expression or serum protein concentration were not detected. Downregulation of relative gene expression was appreciated for individual horses in the M-PO and M-PR treatment arms at select time points.
Considerable variability in measured parameters was detected among horses within and between treatment arms. Misoprostol absorption and systemic exposure after PO administration differed from previous reports in horses not administered LPS. Investigation of multidose administration of misoprostol is warranted to better evaluate efficacy as an anti-inflammatory therapeutic.