Objective—To determine the pharmacokinetics of ciprofloxacin in dogs, including oral absorption following administration of generic ciprofloxacin tablets.
Animals—6 healthy Beagles.
Procedures—In a crossover study design, ciprofloxacin was administered as a generic tablet (250 mg, PO; mean dose, 23 mg/kg) and solution (10 mg/kg, IV) to 6 dogs. In a separate experiment, 4 of the dogs received ciprofloxacin solution (10 mg/mL) PO via stomach tube (total dose, 250 mg). Blood samples were collected before (time 0) and for 24 hours after each dose. Plasma concentrations were analyzed with high-pressure liquid chromatography. Pharmacokinetic analysis was performed by means of compartmental modeling.
Results—When ciprofloxacin was administered as tablets PO, peak plasma concentration was 4.4 μg/mL (coefficient of variation [CV], 55.9%), terminal half-life (t1/2) was 2.6 hours (CV, 10.8%), area under the time-concentration curve was 22.5 μg•h/mL (CV, 62.3%), and systemic absorption was 58.4% (CV, 45.4%). For the dose administered IV, t1/2 was 3.7 hours (CV, 52.3%), clearance was 0.588 L/kg/h (CV, 33.9%), and volume of distribution was 2.39 L/kg (CV, 23.7%). After PO administration as a solution versus IV administration, plasma concentrations were more uniform and consistent among dogs, with absorption of 71% (CV, 7.3%), t1/2 of 3.1 hours (CV, 18.6%), and peak plasma concentration of 4.67 μg/mL (CV, 17.6%).
Conclusions and Clinical Relevance—Inconsistent oral absorption of ciprofloxacin in some dogs may be formulation dependent and affected by tablet dissolution in the small intestine. Because of the wide range in oral absorption of tablets, the dose needed to reach the pharmacokinetic-pharmacodynamic target concentration in this study ranged from 12 to 52 mg/kg (CV, 102%), with a mean dose of 25 mg/kg, once daily, for bacteria with a minimum inhibitory concentration ≤ 0.25 μg/mL.
Objective—To determine the pharmacokinetics and effects of orally administered fluconazole in African grey parrots.
Animals—40 clinically normal Timneh African grey parrots (Psittacus erithacus timneh).
Procedure—In single-dose trials, parrots were placed into groups of 4 to 5 birds each and fluconazole was administered orally at 10 and 20 mg/kg. Blood samples for determination of plasma fluconazole concentrations were collected from each group at 2 or 3 of the following time points: 1, 3, 6, 9, 12, 24, 31, 48, and 72 hours. In multiple-dose trials, fluconazole was administered orally to groups of 5 birds each at doses of 10 and 20 mg/kg every 48 hours for 12 days. Trough plasma concentrations were measured 3 times during treatment. Groups receiving 20 mg/kg were monitored for changes in plasma biochemical analytes, and blood samples were collected on days 1 and 13 of treatment to allow comparison of terminal half-life.
Results—Peak plasma concentrations of fluconazole were 7.45 and 18.59 μg/mL, and elimination half-lives were 9.22 and 10.19 hours for oral administration of 10 and 20 mg/kg, respectively. Oral administration of fluconazole for 12 days at 10 or 20 mg/kg every 48 hours did not cause identifiable adverse effects or change the disposition of fluconazole.
Conclusions and Clinical Relevance—Oral administration of fluconazole to parrots at 10 to 20 mg/kg every 24 to 48 hours maintains plasma concentrations above the minimum inhibitory concentration for several common yeast species. The prolonged dosing interval is an advantage of this treatment regimen.
Objective—To estimate pharmacokinetic variables
and measure tissue fluid concentrations of meropenem
after IV and SC administration in dogs.
Animals—6 healthy adult dogs.
Procedure—Dogs were administered a single dose
of meropenem (20 mg/kg) IV and SC in a crossover
design. To characterize the distribution of meropenem
in dogs and to evaluate a unique tissue fluid collection
method, an in vivo ultrafiltration device was used to
collect interstitial fluid. Plasma, tissue fluid, and urine
samples were analyzed by use of high-performance
liquid chromatography. Protein binding was determined
by use of an ultrafiltration device.
Results—Plasma data were analyzed by compartmental
and noncompartmental pharmacokinetic
methods. Mean ± SD values for half-life, volume of
distribution, and clearance after IV administration for
plasma samples were 0.67 ± 0.07 hours, 0.372 ±
0.053 L/kg, and 6.53 ± 1.51 mL/min/kg, respectively,
and half-life for tissue fluid samples was 1.15 ± 0.57
hours. Half-life after SC administration was 0.98 ±
0.21 and 1.31 ± 0.54 hours for plasma and tissue fluid,
respectively. Protein binding was 11.87%, and
bioavailability after SC administration was 84%.
Conclusions and Clinical Relevance—Analysis of
our data revealed that tissue fluid and plasma
(unbound fraction) concentrations were similar.
Because of the kinetic similarity of meropenem in the
extravascular and vascular spaces, tissue fluid concentrations
can be predicted from plasma concentrations.
We concluded that a dosage of 8 mg/kg, SC,
every 12 hours would achieve adequate tissue fluid
and urine concentrations for susceptible bacteria with
a minimum inhibitory concentration of 0.12 µg/mL.
(Am J Vet Res 2002;63:1622–1628)
Objective—To compare plasma (total and unbound)
and interstitial fluid (ISF) concentrations of doxycycline
and meropenem in dogs following constant rate
IV infusion of each drug.
Animals—6 adult Beagles.
Procedure—Dogs were given a loading dose of
doxycycline and meropenem followed by a constant
rate IV infusion of each drug to maintain an 8-hour
steady state concentration. Interstitial fluid was collected
with an ultrafiltration device. Plasma and ISF
were analyzed by high performance liquid chromatography.
Protein binding and lipophilicity were determined.
Plasma data were analyzed by use of compartmental
Results—Compared with meropenem, doxycycline
had higher protein binding (11.87% [previously published
value] vs 91.75 ± 0.63%) and lipophilicity (partition
coefficients, 0.02 ± 0.01 vs 0.68 ± 0.05). A significant
difference was found between ISF and plasma
total doxycycline concentrations. No significant difference
was found between ISF and plasma unbound
doxycycline concentrations. Concentrations of
meropenem in ISF and plasma (total and unbound)
were similar. Plasma half-life, volume of distribution,
and clearance were 4.56 ± 0.57 hours, 0.65 ± 0.82
L/kg, and 1.66 ± 2.21 mL/min/kg, respectively, for doxycycline
and 0.73 ± 0.07 hours, 0.34 ± 0.06 L/kg, and
5.65 ± 2.76 mL/min/kg, respectively, for meropenem.
The ISF half-life of doxycycline and meropenem was
4.94 ± 0.67 and 2.31 ± 0.36 hours, respectively.
Conclusions and Clinical Relevance—The extent of
protein binding determines distribution of doxycycline
and meropenem into ISF. As a result of high protein
binding, ISF doxycycline concentrations are lower
than plasma total doxycycline concentrations.
Concentrations of meropenem in ISF can be predicted
from plasma total meropenem concentrations.
(Am J Vet Res 2003;64:1040–1046)
Objective—To compare pharmacokinetics of
enrofloxacin administered IV and in various oral preparations
Animals—5 mature Katahdin ewes weighing 42 to 50
Procedure—Ewes received 4 single-dose treatments
of enrofloxacin in a nonrandomized crossover design
followed by a multiple-dose oral regimen. Single-dose
treatments consisted of an IV bolus of enrofloxacin
(5 mg/kg), an oral drench (10 mg/kg) made from
crushed enrofloxacin tablets, oral administration in
feed (10 mg/kg; mixture of crushed enrofloxacin
tablets and grain), and another type of oral administration
in feed (10 mg/kg; mixture of enrofloxacin solution
and grain). The multiple-dose regimen consisted of
feeding a mixture of enrofloxacin solution and grain (10
mg/kg, q 24 h, for 7 days). Plasma concentrations of
enrofloxacin and ciprofloxacin were measured by use
of high-performance liquid chromatography.
Results—Harmonic mean half-life for oral administration
was 14.80, 10.80, and 13.07 hours, respectively,
for the oral drench, crushed tablets in grain, and
enrofloxacin solution in grain. Oral bioavailability for the
oral drench, crushed tablets in grain, and enrofloxacin
in grain was 47.89, 98.07, and 94.60%, respectively,
and median maximum concentration (Cmax) was 1.61,
2.69, and 2.26 µg/ml, respectively. Median Cmax of the
multiple-dose regimen was 2.99 µg/ml.
Conclusions and Clinical Relevance—Enrofloxacin
administered orally to sheep has a prolonged half-life
and high oral bioavailability. Oral administration at 10
mg/kg, q 24 h, was sufficient to achieve a plasma concentration
of 8 to 10 times the minimum inhibitory
concentration (MIC) of any microorganism with an
MIC ≤ 0.29 µg/ml. (Am J Vet Res 2002;
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 of posaconazole in dogs given an IV solution, oral suspension, and delayed-release tablet.
ANIMALS 6 healthy dogs.
PROCEDURES Posaconazole was administered IV (3 mg/kg) and as an oral suspension (6 mg/kg) to dogs in a randomized crossover study. Blood samples were collected before (time 0) and for 48 hours after each dose. In an additional experiment, 5 of the dogs received posaconazole delayed-release tablets (mean dose, 6.9 mg/kg); blood samples were collected for 96 hours. Plasma concentrations were analyzed with high-performance liquid chromatography.
RESULTS IV solution terminal half-life (t1/2) was 29 hours (coefficient of variation [CV], 23%). Clearance and volume of distribution were 78 mL/h/kg (CV, 59%) and 3.3 L/kg (CV, 38%), respectively. Oral suspension t1/2 was 24 hours (CV, 42%). Maximum plasma concentration (Cmax) of 0.42 μg/mL (CV, 56%) was obtained at 7.7 hours (CV, 92%). Mean bioavailability was 26% (range, 7.8% to 160%). Delayed-release tablet t1/2 was 42 hours (CV, 25%), with a Cmax of 1.8 μg/mL (CV, 44%) at 9.5 hours (CV, 85%). Mean bioavailability of tablets was 159% (range, 85% to 500%). Bioavailability of delayed-release tablets was 497% (range, 140% to 1,800%) relative to that of the oral suspension.
CONCLUSIONS AND CLINICAL RELEVANCE Absorption of posaconazole oral suspension in dogs was variable. Absorption of the delayed-release tablets was greater than absorption of the oral suspension, with a longer t1/2 that may favor its clinical use in dogs. Administration of delayed-release tablets at a dosage of 5 mg/kg every other day can be considered for future studies.
Objective—To determine plasma concentrations of
enrofloxacin and the active metabolite ciprofloxacin
after PO, SC, and IV administration of enrofloxacin to
Animals—6 adult female alpacas.
Procedure—A crossover design was used for administration
of 3 single-dose treatments of enrofloxacin
to alpacas, which was followed by an observational
14-day multiple-dose regimen. Single-dose treatments
consisted of IV and SC administration of
injectable enrofloxacin (5 mg/kg) and PO administration
of enrofloxacin tablets (10 mg/kg) dissolved in
grain to form a slurry. Plasma enrofloxacin concentrations
were measured by use of high-performance liquid
chromatography. The multiple-dose regimen consisted
of feeding a mixture of crushed and moistened
enrofloxacin tablets mixed with grain. Behavior,
appetite, and fecal quality were monitored throughout
the 14-day treatment regimen and for 71 additional
days following treatment.
Results—Mean half-life following IV, SC, and PO
administration was 11.2, 8.7, and 16.1 hours, respectively.
For SC and PO administration, mean total systemic
availability was 90.18% and 29.31%, respectively;
mean maximum plasma concentration was
3.79 and 1.81 µg/mL, respectively; and area under the
curve (AUC) was 50.05 and 33.97 (µg × h)/mL,
respectively. The SC or PO administration of a single
dose of enrofloxacin yielded a ratio for AUC to minimum
inhibitory concentration > 100 for many grampositive
and gram-negative bacterial pathogens common
Conclusions and Clinical Relevance—The administration
of enrofloxacin (5 mg/kg, SC, or 10 mg/kg, PO)
may be appropriate for antimicrobial treatment of
alpacas. (Am J Vet Res 2005;66:767–771)
Objective—To assess the use of a von Frey device as
a mechanical nociceptive stimulus for evaluation of
the antinociceptive effects of morphine in dogs and
its potential application in the pharmacodynamic modeling
of morphine in that species.
Animals—6 healthy Beagles.
Procedure—von Frey thresholds were measured in
all dogs before and at intervals after they received no
treatment (control dogs) and IV administration of morphine
sulfate (1 mg/kg; treated dogs) in a crossover
study. The von Frey device consisted of a rigid tip
(0.5 mm in diameter) and an electronic load cell; the
operator was unaware of recorded measurements.
Results—Application of the von Frey device was
simple and well tolerated by all dogs and caused no
apparent tissue damage. No significant changes in
thresholds were detected in the control dogs at 8
hourly measurements, indicating a lack of acquired
tolerance, learned aversion, or local hyperalgesia.
When assessed as a group, treated dogs had significantly
high thresholds for 4 hours following morphine
administration, compared with baseline values;
individually, thresholds decreased to baseline
values within (mean ± SE) 2.8 ± 0.6 hours. The
maximal effect (change from baseline values) was
213 ± 43%, and the plasma morphine concentration
to achieve 50% maximal effect was
13.92 ± 2.39 ng/mL.
Conclusions and Clinical Relevance—Data suggest
that, in dogs, evaluation of the antinociceptive effect
and pharmacodynamic modeling of a dose of morphine
sulfate (1 mg/kg, IV) can be successfully
achieved by use of a von Frey device. (Am J Vet Res
Objective—To determine the pharmacokinetics of
itraconazole after IV or oral administration of a solution
or capsules to horses and to examine disposition
of itraconazole in the interstitial fluid (ISF), aqueous
humor, and polymorphonuclear leukocytes after oral
administration of the solution.
Animals—6 healthy horses.
Procedure—Horses were administered itraconazole
solution (5 mg/kg) by nasogastric tube, and samples of
plasma, ISF, aqueous humor, and leukocytes were
obtained. Horses were then administered itraconazole
capsules (5 mg/kg), and plasma was obtained. Three
horses were administered itraconazole (1.5 mg/kg, IV),
and plasma samples were obtained. All samples were
analyzed by use of high-performance liquid chromatography.
Plasma protein binding was determined. Data
were analyzed by compartmental and noncompartmental
Results—Itraconazole reached higher mean ± SD
plasma concentrations after administration of the
solution (0.41 ± 0.13 µg/mL) versus the capsules
(0.15 ± 0.12 µg/mL). Bioavailability after administration
of capsules relative to solution was 33.83 ±
33.08%. Similar to other species, itraconazole has a
high volume of distribution (6.3 ± 0.94 L/kg) and a
long half-life (11.3 ± 2.84 hours). Itraconazole was not
detected in the ISF, aqueous humor, or leukocytes.
Plasma protein binding was 98.81 ± 0.17%.
Conclusions and Clinical Relevance—Itraconazole
administered orally as a solution had higher, more
consistent absorption than orally administered capsules
and attained plasma concentrations that are
inhibitory against fungi that infect horses.
Administration of itraconazole solution (5 mg/kg, PO,
q 24 h) is suggested for use in clinical trials to test the
efficacy of itraconazole in horses. (Am J Vet Res