Procedure—Mitogen-stimulated lymphocyte proliferation
in whole blood incubated with and without various
concentrations of cyclosporine, tacrolimus,
sirolimus, mycophenolic acid (MPA), or A771726 was
measured by use of [3H]thymidine incorporation. Drug
concentrations that resulted in a 50% inhibition of
mitogen-induced proliferation (IC50) were calculated.
Lymphocyte viability was determined by use of the trypan blue dye exclusion method.
Results—An obvious dose-response relationship for
the antiproliferative effects of each drug was detected.
Mean IC50 determined with concanavalin A was
46 nMfor cyclosporine, 9 nMfor tacrolimus, 12 nM
for sirolimus, 16 nM for MPA, and 30 mM for
A771726, whereas with pokeweed mitogen, mean
IC50 was 33 nM for cyclosporine, 5 nMfor tacrolimus,
15 nM for sirolimus, 14 nM for mycophenolic acid,
and 25 mM for A771726. Mitogen-stimulated and
nonstimulated lymphocytes remained viable, regardless
of drug evaluated.
Conclusions and Clinical Relevance—Tacrolimus,
sirolimus, MPA, and A771726 inhibited in vitro mitogen-
stimulated proliferation of feline lymphocytes in a
dose-dependent manner. These novel immunosuppressive
drugs may be useful for management of
immune-mediated inflamMatory diseases and prevention
and treatment of rejection in cats that undergo
organ transplantation. (Am J Vet Res 2000;61:
Objective—To develop a flow-limited, physiologicbased
pharmacokinetic model for use in estimating
concentrations of sulfamethazine after IV administration
Sample Population—4 published studies provided
physiologic values for organ weights, blood flows,
clearance, and tissue-to-blood partition coefficients,
and 3 published studies provided data on plasma and
other tissue compartments for model validation.
Procedure—For the parent compound, the model
included compartments for blood, adipose, muscle,
liver, and kidney tissue with an extra compartment
representing the remaining carcass. Compartments
for the N-acetyl metabolite included the liver and the
remaining body. The model was created and optimized
by use of computer software. Sensitivity
analysis was completed to evaluate the importance
of each constant on the whole model. The model was
validated and used to estimate a withhold interval
after an IV injection at a dose of 50 mg/kg. The withhold
interval was compared to the interval estimated
by the Food Animal Residue Avoidance Databank
Results—Specific tissue correlations for plasma, adipose,
muscle, kidney, and liver tissue compartments
were 0.93, 0.86, 0.99, 0.94, and 0.98, respectively.
The model typically overpredicted concentrations at
early time points but had excellent accuracy at later
time points. The withhold interval estimated by use of
the model was 120 hours, compared with 100 hours
estimated by FARAD.
Conclusions and Clinical Relevance—Use of this
model enabled accurate prediction of sulfamethazine
pharmacokinetics in swine and has applications for
food safety and prediction of drug residues in edible
tissues. (Am J Vet Res 2005;66:1686–1693)
Objective—To determine the antimicrobial susceptibility of common respiratory tract pathogens from sheep and goats.
Sample Population—41 respiratory tract isolates from sheep and 36 isolates from goats.
Procedures—Disk diffusion assay was used to determine antimicrobial susceptibility of isolates to amoxicillin-clavulanic acid, ceftiofur, ciprofloxacin, florfenicol, and tetracycline. Minimum inhibitory concentrations of florfenicol for these isolates were determined by use of the microbroth dilution technique.
Results—The most common isolates were Pasteurella multocida (n = 28) and Mannheimia haemolytica (39). All isolates were susceptible to amoxicillin-clavulanic acid, ceftiofur, ciprofloxacin, and florfenicol. Five percent (4/77) of isolates were resistant to tetracycline.
Conclusions and Clinical Relevance—Susceptibility of respiratory tract pathogens isolated from sheep and goats to commonly used antimicrobial drugs in this study was high. Treatment of these species for bacterial respiratory tract disease is likely not complicated by antimicrobial resistance.
Objective—To determine the pharmacokinetics of butorphanol tartrate after IV and IM single-dose administration in red-tailed hawks (RTHs) and great horned owls (GHOs).
Animals—6 adult RTHs and 6 adult GHOs.
Procedures—Each bird received an injection of butorphanol (0.5 mg/kg) into either the right jugular vein (IVj) or the pectoral muscles in a crossover study (1-week interval between treatments). The GHOs also later received butorphanol (0.5 mg/kg) via injection into a medial metatarsal vein (IVm). During each 24-hour postinjection period, blood samples were collected from each bird; plasma butorphanol concentrations were determined via liquid chromatography-mass spectrometry.
Results—2- and 1-compartment models best fit the IV and IM pharmacokinetic data, respectively, in both species. Terminal half-lives of butorphanol were 0.94 ± 0.30 hours (IVj) and 0.94 ± 0.26 hours (IM) for RTHs and 1.79 ± 1.36 hours (IVj), 1.84 ± 1.56 hours (IM), and 1.19 ± 0.34 hours (IVm) for GHOs. In GHOs, area under the curve (0 to infinity) for butorphanol after IVj or IM administration exceeded values in RTHs; GHO values after IM and IVm administration were less than those after IVj administration. Plasma butorphanol clearance was significantly more rapid in the RTHs. Bioavailability of butorphanol administered IM was 97.6 ± 33.2% (RTHs) and 88.8 ± 4.8% (GHOs).
Conclusions and Clinical Relevance—In RTHs and GHOs, butorphanol was rapidly absorbed and distributed via all routes of administration; the drug's rapid terminal half-life indicated that published dosing intervals for birds may be inadequate in RTHs and GHOs.
Objective—To describe pharmacokinetics of multidose
oral administration of tacrolimus in healthy cats
and evaluate the efficacy of tacrolimus in the prevention
of allograft rejection in cats with renal transplants.
Animals—6 healthy research cats.
Procedure—Cats received tacrolimus (0.375 mg/kg,
PO, q 12 h) for 14 days. Blood tacrolimus concentrations
were measured by a high performance liquid
chromatography-mass spectrometry assay. Each cat
received an immunogenically mismatched renal allograft
and native kidney nephrectomy. Tacrolimus
dosage was modified to maintain a target blood concentration
of 5 to 10 ng/mL. Cats were euthanatized
if plasma creatinine concentration exceeded 7 mg/dL,
body weight loss exceeded 20%, or on day 50 after
surgery. Kaplan-Meier survival curves were plotted for
6 cats treated with tacrolimus and for 8 cats with
renal transplants that did not receive immunosuppressive
Results—Mean (± SD) values of elimination half-life,
time to maximum concentration, maximum blood concentration,
and area under the concentration versus
time curve from the last dose of tacrolimus to 12 hours
later were 20.5 ± 9.8 hours, 0.77 ± 0.37 hours, 27.5 ±
31.8 ng/mL, and 161 ± 168 hours × ng/mL, respectively.
Tacrolimus treated cats survived longer (median, 44
days; range, 24 to 52 days) than untreated cats (median,
23 days; range, 8 to 34 days). On histologic evaluation,
3 cats had evidence of acute-active rejection, 1 cat
had necrotizing vasculitis, and 2 cats euthanatized at
study termination had normal appearing allografts.
Conclusions and Clinical Relevance—Tacrolimus
may be an effective immunosuppressive agent for
renal transplantation in cats. (Am J Vet Res 2003;64:926–934)
Objective—To investigate the feasibility of using multivariate
cluster analysis to meta-analyze pharmacokinetic
data obtained from studies of pharmacokinetics
of ampicillin trihydrate in cattle and identify factors
that could account for variability in pharmacokinetic
parameters among studies.
Sample Population—Data from original studies of
the pharmacokinetics of ampicillin trihydrate in cattle
in the database of the Food Animal Residue
Procedure—Mean plasma or serum ampicillin concentration
versus time data and potential factors that
may have affected the pharmacokinetics of ampicillin
trihydrate were obtained from each study.
Noncompartmental pharmacokinetic analyses were
performed, and values of pharmacokinetic parameters
were clustered by use of multivariate cluster
analysis. Practical importance of the clusters was
evaluated by comparing the frequency of factors that
may have affected the pharmacokinetics of ampicillin
trihydrate among clusters.
Results—A single cluster with lower mean values for
clearance and volume of distribution of ampicillin trihydrate
administered PO, compared with other clusters,
was identified. This cluster included studies that
used preruminant calves in which feeding was withheld
overnight and calves to which probenecid had
been administered concurrently.
Conclusions and Clinical Relevance—Meta-analysis
was successful in detecting a potential subpopulation
of cattle for which factors that explained differences in
pharmacokinetic parameters could be identified.
Accurate estimates of pharmacokinetic parameters
are important for the calculation of dosages and
extended withdrawal intervals after extralabel drug
administration. (Am J Vet Res 2005;66:108–112)
Objective—To determine the pharmacokinetics of
ceftiofur sodium after IM and SC administration in
Animals—6 male and 4 female adult green iguanas.
Procedure—In a crossover design, 5 iguanas
received a single dose of ceftiofur sodium (5 mg/kg)
IM, and 5 iguanas received the same dose SC. Blood
samples were taken at 0, 20, and 40 minutes and 1,
2, 4, 8, 24, 48, and 72 hours after administration. After
a 10-week washout period, each iguana was given the
same dose via the reciprocal administration route,
and blood was collected in the same fashion.
Ceftiofur free-acid equivalents were measured via
high-performance liquid chromatography.
Results—The first phase intercepts were significantly
different between the 2 administration routes.
Mean maximum plasma concentration was significantly
higher with the IM (28.6 ± 8.0 µg/mL) than the
SC (18.6 ± 8.3 µg/mL) administration route. There
were no significant differences between terminal halflives
(harmonic mean via IM route, 15.7 ± 4.7 hours;
harmonic mean via SC route, 19.7 ± 6.7 hours) and
mean areas under the curve measured to the last
time point (IM route, 11,722 ± 7,907 µg·h/mL; SC
route, 12,143 ± 9,633 µg·h/mL). Ceftiofur free-acid
equivalent concentrations were maintained ≥ 2 µg/mL
for > 24 hours via both routes.
Conclusions and Clinical Relevance—A suggested
dosing schedule for ceftiofur sodium in green iguanas
for microbes susceptible at > 2 µg/mL would be 5
mg/kg, IM or SC, every 24 hours. (Am J Vet Res 2003;64:1278–1282)