Objective—To determine pharmacodynamic and pharmacokinetic properties of clopidogrel and the metabolite SR 26334 in dogs.
Animals—9 mixed-breed dogs.
Procedures—8 dogs received clopidogrel (mean ± SD 1.13 ± 0.17 mg/kg, PO, q 24 h) for 3 days; 5 of these dogs subsequently received a lower dose of clopidogrel (0.5 ± 0.18 mg/kg, PO, q 24 h) for 3 days. Later, 5 dogs received clopidogrel (1.09 ± 0.12 mg/kg, PO, q 24 h) for 5 days. Blood samples were collected for optical platelet aggregometry, citrated native and platelet mapping thrombelastography (TEG), and measurement of plasma drug concentrations. Impedance aggregometry was performed on samples from 3 dogs in each 3-day treatment group.
Results—ADP-induced platelet aggregation decreased (mean ± SD 93 ± 6% and 80 ± 22% of baseline values, respectively) after 72 hours in dogs in both 3-day treatment groups; duration of effect ranged from > 3 to > 7 days. Platelet mapping TEG and impedance aggregometry yielded similar results. Citrated native TEG was not different among groups. Clopidogrel was not detected in any samples; in dogs given 1.13 ± 0.17 mg/kg, maximum concentration of SR 26334 (mean ± SD, 0.206 ± 0.2 μg/mL) was detected 1 hour after administration.
Conclusions and Clinical Relevance—Clopidogrel inhibited ADP-induced platelet aggregation in healthy dogs and may be a viable antiplatelet agent for use in dogs.
Impact for Human Medicine—Pharmacodynamic effects of clopidogrel in dogs were similar to effects reported in humans; clopidogrel may be useful in studies involving dogs used to investigate human disease.
To evaluate the effects of housing environment on oral absorption of acetaminophen in dogs.
6 healthy Beagles.
Acetaminophen (325 mg, PO; mean dose, 31.1 mg/kg) was administered in a crossover study design with dogs housed in their normal environment or in a cage in an unfamiliar environment. There was a 7-day washout period between phases. Blood samples were collected for 24 hours following acetaminophen administration, and plasma acetaminophen concentrations were determined with high-pressure liquid chromatography.
A 2-compartment model with lag time was the best fit for both phases of the study. None of the primary or secondary pharmacokinetic parameters were significantly different between the 2 housing environments.
Findings suggested that in dogs, housing environment (normal environment vs a cage in an unfamiliar environment) did not significantly affect oral absorption and, by extension, gastric emptying of acetaminophen.
OBJECTIVE To determine the pharmacokinetics of detomidine hydrochloride administered IV (as an injectable formulation) or by the oral-transmucosal (OTM) route (as a gel) and assess sedative effects of the OTM treatment in healthy dogs.
ANIMALS 12 healthy adult dogs.
PROCEDURES In phase 1, detomidine was administered by IV (0.5 mg/m2) or OTM (1 mg/m2) routes to 6 dogs. After a 24-hour washout period, each dog received the alternate treatment. Blood samples were collected for quantification via liquid chromatography with mass spectrometry and pharmacokinetic analysis. In phase 2, 6 dogs received dexmedetomidine IV (0.125 mg/m2) or detomidine gel by OTM administration (0.5 mg/m2), and sedation was measured by a blinded observer using 2 standardized sedation scales while dogs underwent jugular catheter placement. After a l-week washout period, each dog received the alternate treatment.
RESULTS Median maximum concentration, time to maximum concentration, and bioavailability for detomidine gel following OTM administration were 7.03 ng/mL, 1.00 hour, and 34.52%, respectively; harmonic mean elimination half-life was 0.63 hours. All dogs were sedated and became laterally recumbent with phase 1 treatments. In phase 2, median global sedation score following OTM administration of detomidine gel was significantly lower (indicating a lesser degree of sedation) than that following IV dexmedetomidine treatment; however, total sedation score during jugular vein catheterization did not differ between treatments. The gel was subjectively easy to administer, and systemic absorption was sufficient for sedation.
CONCLUSIONS AND CLINICAL RELEVANCE Detomidine gel administered by the OTM route provided sedation suitable for a short, minimally invasive procedure in healthy dogs.
OBJECTIVE To determine pharmacokinetics and adverse effects after voriconazole administration to cats and identify an oral dose of voriconazole for cats that maintains plasma drug concentrations within a safe and effective range.
ANIMALS 6 healthy cats.
PROCEDURES Voriconazole (1 mg/kg, IV) was administered to each cat (phase 1). Serial plasma voriconazole concentrations were measured for 24 hours after administration. Voriconazole suspension or tablets were administered orally at 4, 5, or 6 mg/kg (phase 2). Plasma voriconazole concentrations were measured for 24 hours after administration. Pharmacokinetics of tablet and suspension preparations was compared. Finally, an induction dose of 25 mg/cat (4.1 to 5.4 mg/kg, tablet formulation), PO, was administered followed by 12.5 mg/cat (2.05 to 2.7 mg/kg), PO, every 48 hours for 14 days (phase 3). Plasma voriconazole concentration was measured on days 2, 4, 8, and 15.
RESULTS Voriconazole half-life after IV administration was approximately 12 hours. Maximal plasma concentration was reached within 60 minutes after oral administration. A dose of 4 mg/kg resulted in plasma concentrations within the target range (1 to 4 μg/mL). Adverse effects included hypersalivation and miosis. During long-term administration, plasma concentrations remained in the target range but increased, which suggested drug accumulation.
CONCLUSIONS AND CLINICAL RELEVANCE Voriconazole had excellent oral bioavailability and a long half-life in cats. Oral administration of a dose of 12.5 mg/cat every 72 hours should be investigated. Miosis occurred when plasma concentrations reached the high end of the target range. Therefore, therapeutic drug monitoring should be considered to minimize adverse effects.
OBJECTIVE To compare absorption characteristics of orally administered compounded itraconazole capsules and suspension with those of reference (brand-name) formulations in healthy cats.
DESIGN Randomized crossover study.
ANIMALS 8 healthy adult cats.
PROCEDURES After 12 hours of food withholding, cats received 50 mg of itraconazole (reference capsule, reference solution, compounded capsule, and compounded suspension) in a randomized crossover design, with a 21-day washout period. Capsules were administered with a small meal. Blood samples were collected at predetermined intervals for high-pressure liquid chromatography analysis of plasma itraconazole concentrations. Area under the concentration-time curve, maximum concentration, and terminal half-life of itraconazole were determined and compared among formulations.
RESULTS 7 cats completed the study. Mean half-life of itraconazole in reference formulations was 18 to 26 hours. Absorption of the reference solution was 3 times that of the reference capsule. Compounded formulations were absorbed poorly and inconsistently. Complete pharmacokinetic results for the compounded capsule were obtained for only 3 of 6 cats and for the compounded suspension for only 1 of 5 cats, precluding bioequivalence analysis. Relative absorption of compounded formulations was only 2% to 8% of reference formulation values.
CONCLUSIONS AND CLINICAL RELEVANCE Compounded oral formulations of itraconazole should not be used for cats because of poor absorption. The differences in absorption between the 2 reference formulations suggested that doses required to meet human target serum concentrations in cats are markedly different (capsules, 12.5 mg/kg [5.7 mg/lb], q 24 h, with food; solution, 4 mg/kg [1.8 mg/lb], q 24 h, without food).
Objective—To define the pharmacokinetics of florfenicol in synovial fluid (SYNF) and serum from central venous (CV) and digital venous (DV) blood samples following regional IV perfusion (RIVP) of the distal portion of the hind limb in cows.
Animals—6 healthy adult cows.
Procedures—In each cow, IV catheters were placed in the dorsal common digital vein (DCDV) and the plantar vein of the lateral digit, and an indwelling catheter was placed in the metatarsophalangeal joint of the left hind limb. A pneumatic tourniquet was applied to the midmetatarsal region. Florfenicol (2.2 mg/kg) was administered into the DCDV. Samples of DV blood, SYNF, and CV (jugular) blood were collected after 0.25, 0.50, and 0.75 hours, and the tourniquet was removed; additional samples were collected at intervals for 24 hours after infusion. Florfenicol analysis was performed via high-performance liquid chromatography.
Results—In DV blood, CV blood, and SYNF, mean ± SD maximum florfenicol concentration was 714.79 ± 301.93 μg/mL, 5.90 ± 1.37 μg/mL, and 39.19 ± 29.42 μg/mL, respectively; area under the concentration versus time curve was 488.14 ± 272.53 h•μg•mL−1, 23.10 ± 6.91 h•μg•mL−1, and 113.82 ± 54.71 h•μg•mL−1, respectively; and half-life was 4.09 ± 1.93 hours, 4.77 ± 0.67 hours, and 3.81 ± 0.81 hours, respectively.
Conclusions and Clinical Relevance—Following RIVP, high florfenicol concentrations were achieved in DV blood and SYNF, whereas the CV blood concentration remained low. In cattle, RIVP of florfenicol may be useful in the treatment of infectious processes involving the distal portion of limbs.
Objective—To evaluate plasma glipizide concentration
and its relationship to plasma glucose and serum
insulin concentrations in healthy cats administered
glipizide orally or transdermally.
Animals—15 healthy adult laboratory-raised cats.
Procedure—Cats were randomly assigned to 2 treatment
groups (5 mg of glipizide, PO or transdermally)
and a control group. Blood samples were collected 0,
10, 20, 30, 45, 60, 90, and 120 minutes and 4, 6, 10,
14, 18, and 24 hours after administration to determine
concentrations of insulin, glucose, and glipizide.
Results—Glipizide was detected in all treated cats.
Mean ± SD transdermal absorption was 20 ± 14% of
oral absorption. Mean maximum glipizide concentration
was reached 5.0 ± 3.5 hours after oral and 16.0 ±
4.5 hours after transdermal administration. Elimination
half-life was variable (16.8 ± 12 hours orally
and 15.5 ± 15.3 hours transdermally). Plasma glucose
concentrations decreased in all treated cats, compared
with concentrations in control cats. Plasma glucose
concentrations were significantly lower 2 to 6
hours after oral administration, compared with after
transdermal application; concentrations were similar
between treatment groups and significantly lower
than for control cats 10 to 24 hours after treatment.
Conclusions and Clinical Relevance—Transdermal
absorption of glipizide was low and inconsistent, but
analysis of our results indicated that it did affect plasma
glucose concentrations. Transdermal administration
of glipizide is not equivalent to oral administration.
Formulation, absorption, and stability studies are
required before clinical analysis can be performed.
Transdermal administration of glipizide cannot be recommended
for clinical use at this time. (Am J Vet Res 2005;66:581–588)
Objective—To determine the pharmacokinetics of
enrofloxacin in neonatal kittens and compare the pharmacokinetics
of enrofloxacin in young and adult cats.
Animals—7 adult cats and 111 kittens (2 to 8 weeks
Procedure—A single dose of 5 mg of enrofloxacin/kg
was administered to adults (IV) and kittens (IV, SC, or
PO). Plasma concentrations of enrofloxacin and its
active metabolite, ciprofloxacin, were determined.
Results—The half-life of enrofloxacin administered IV
in 2-, 6-, and 8-week-old kittens was significantly
shorter and its elimination rate significantly greater
than that detected in adults. The apparent volumes of
distribution were lower at 2 to 4 weeks and greater at
6 to 8 weeks. This resulted in lower peak plasma concentration
(Cmax) at 6 to 8 weeks; however, initial plasma
concentration was within the therapeutic range
after IV administration at all ages. Compared with IV
administration, SC injection of enrofloxacin in 2-weekold
kittens resulted in similar Cmax, half-life, clearance,
and area under the curve values. Enrofloxacin administered
via SC injection was well absorbed in 6- and 8-
week-old kittens, but greater clearance and apparent
volume of distribution resulted in lower plasma concentrations.
Oral administration of enrofloxacin resulted
in poor bioavailability.
Conclusions and Clinical Relevance—In neonatal
kittens, IV and SC administration of enrofloxacin provided
an effective route of administration. Oral administration
of enrofloxacin in kittens did not result in
therapeutic drug concentrations. Doses may need to
be increased to achieve therapeutic drug concentrations
in 6- to 8-week-old kittens. ( Am J Vet Res 2004;65:350–356)
Objective—To determine whether infection with
Tritrichomonas foetus causes diarrhea in specific pathogen-free or Cryptosporidium coinfected cats.
Animals—4 cats with subclinical cryptosporidiosis
(group 1) and 4 specific-pathogen-free cats (group 2).
Procedure—Cats were infected orogastrically with an
axenic culture of T foetus isolated from a kitten with
diarrhea. Direct microscopy and protozoal culture of
feces, fecal character, serial colonic mucosal biopsy
specimens, and response to treatment with nitazoxanide
(NTZ; group 1) or prednisolone (groups 1 and 2)
Results—Infection with T foetus persisted in all cats
for the entire 203-day study and resulted in diarrhea
that resolved after 7 weeks. Group-1 cats had an earlier
onset, more severe diarrhea, and increased number
of trichomonads on direct fecal examination, compared
with group-2 cats. Use of NTZ eliminated shedding
of T foetus and Cryptosporidium oocysts, but
diarrhea consisting of trichomonad-containing feces
recurred when treatment was discontinued.
Prednisolone did not have an effect on infection with
T foetus but resulted in reappearance of
Cryptosporidium oocysts in the feces of 2 of 4 cats.
During necropsy, T foetus was isolated from contents
of the ileum, cecum, and colon. Tritrichomonas foetus
organisms and antigen were detected on surface
epithelia and within superficial detritus of the cecal
and colonic mucosa.
Conclusions and Clinical Relevance—After experimental
inoculation in cats, T foetus organisms colonize
the ileum, cecum, and colon, reside in close contact
with the epithelium, and are associated with transient
diarrhea that is exacerbated by coexisting cryptosporidiosis
but not treatment with prednisolone.
(Am J Vet Res 2001;62:1690–1697)
Objective—To determine the efficacy of tinidazole for treatment of cats with experimentally induced Tritrichomonas foetus infection.
Animals—8 specific-pathogen-free kittens.
Procedures—Tinidazole was tested for activity against a feline isolate of T foetus in vitro. Kittens were infected orogastrically with the same isolate and treated or not with tinidazole (30 mg/kg, PO, q 24 h for 14 days). Amoxicillin was administered 28 weeks after completion of tinidazole administration to induce diarrhea. Feces were repeatedly tested for T foetus by use of PCR assay and microbial culture for 33 weeks.
Results—Tinidazole killed T foetus at concentrations ≥ 10 μg/mL in vitro. In experimentally induced infection, tinidazole administered at 30 mg/kg decreased T foetus below the limit of molecular detection in 2 of 4 cats. Recrudescent shedding of T foetus, as elicited by amoxicillin-induced diarrhea, was diminished in cats that received prior treatment with tinidazole.
Conclusions and Clinical Relevance—Although tinidazole decreased the detection of T foetus and treated cats were resistant to later efforts to incite the infection, inability of tinidazole to eradicate infection in many cats poses a serious impediment to the drug’s effectiveness in practice.