Objective—To model the plasma tetracycline concentrations in swine (Sus scrofa domestica) treated with medication administered in water and determine the factors that contribute to the most accurate predictions of measured plasma drug concentrations.
Sample—Plasma tetracycline concentrations measured in blood samples from 3 populations of swine.
Procedures—Data from previous studies provided plasma tetracycline concentrations that were measured in blood samples collected from 1 swine population at 0, 4, 8, 12, 24, 32, 48, 56, 72, 80, 96, and 104 hours and from 2 swine populations at 0, 12, 24, 48, and 72 hours hours during administration of tetracycline hydrochloride dissolved in water. A 1-compartment pharmacostatistical model was used to analyze 5 potential covariate schemes and determine factors most important in predicting the plasma concentrations of tetracycline in swine.
Results—2 models most accurately predicted the tetracycline plasma concentrations in the 3 populations of swine. Factors of importance were body weight or age of pig, ambient temperature, concentration of tetracycline in water, and water use per unit of time.
Conclusions and Clinical Relevance—The factors found to be of importance, combined with knowledge of the individual pharmacokinetic and chemical properties of medications currently approved for administration in water, may be useful in more prudent administration of approved medications administered to swine. Factors found to be important in pharmacostatistical models may allow prediction of plasma concentrations of tetracycline or other commonly used medications administered in water. The ability to predict in vivo concentrations of medication in a population of food animals can be combined with bacterial minimum inhibitory concentrations to decrease the risk of developing antimicrobial resistance.
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 pharmacokinetics of marbofloxacin after oral administration in juvenile harbor seals (Phoca vitulina) at a dose of 5 mg/kg (2.3 mg/lb) and to compare pharmacokinetic variables after pharmacokinetic analysis by naïve averaged, naïve pooled, and nonlinear mixed-effects modeling.
Animals—33 male and 22 female juvenile seals being treated for various conditions.
Procedures—Blood collection was limited to ≤ 3 samples/seal. Plasma marbofloxacin concentrations were measured via high-pressure liquid chromatography with UV detection.
Results—Mean ± SE dose of marbofloxacin administered was 5.3 ± 0.1 mg/kg (2.4 ± 0.05 mg/lb). The terminal half-life, volume of distribution (per bioavailability), and clearance (per bioavailability) were approximately 5 hours, approximately 1.4 L/kg, and approximately 3 mL/min/kg, respectively (values varied slightly with the method of calculation). Maximum plasma concentration and area under the plasma-time concentration curve were approximately 3 μg/mL and 30 h·μg/mL, respectively. Naïve averaged and naïve pooled analysis appeared to yield a better fit to the population, but nonlinear mixed-effects modeling yielded a better fit for individual seals.
Conclusions and Clinical Relevance—Values of pharmacokinetic variables were similar regardless of the analytic method used. Pharmacokinetic variability can be assessed with nonlinear mixed-effects modeling, but not with naïve averaged or naïve pooled analysis. Visual observation by experienced trainers revealed no adverse effects in treated seals. Plasma concentrations attained with a dosage of 5 mg/kg every 24 hours would be expected to be efficacious for treatment of infections caused by susceptible bacteria (excluding Pseudomonas aeruginosa).
Objective—To determine whether pharmacokinetics and milk elimination of flunixin and 5-hydroxy flunixin differed between healthy and mastitic cows.
Design—Prospective controlled clinical trial.
Animals—20 lactating Holstein cows.
Procedures—Cows with mastitis and matched control cows received flunixin IV, ceftiofur IM, and cephapirin or ceftiofur, intramammary. Blood samples were collected before (time 0) and 0.25, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours after flunixin administration. Composite milk samples were collected at 0, 2, 12, 24, 36, 48, 60, 72, 84, and 96 hours. Plasma and milk samples were analyzed by use of ultra–high-performance liquid chromatography with mass spectrometric detection.
Results—For flunixin in plasma samples, differences in area under the concentration-time curve and clearance were detected between groups. Differences in flunixin and 5-hydroxy flunixin concentrations in milk were detected at various time points. At 36 hours after flunixin administration (milk withdrawal time), 8 cows with mastitis had 5-hydroxy flunixin concentrations higher than the tolerance limit (ie, residues). Flunixin residues persisted in milk up to 60 hours after administration in 3 of 10 mastitic cows.
Conclusions and Clinical Relevance—Pharmacokinetics and elimination of flunixin and 5-hydroxy flunixin in milk differed between mastitic and healthy cows, resulting in violative residues. This may partially explain the high number of flunixin residues reported in beef and dairy cattle. This study also raised questions as to whether healthy animals should be used when determining withdrawal times for meat and milk.
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 elimination kinetics of
ceftiofur hydrochloride in milk after intramammary
administration in lactating dairy cows.
Animals—5 lactating dairy cows.
Procedure—After collection of baseline milk samples,
300 mg (6 mL) of ceftiofur was infused into the
left front and right rear mammary gland quarters of
each cow. Approximately 12 hours later, an additional
300 mg of ceftiofur was administered into the
same mammary gland quarters after milking. Milk
samples were collected from each mammary gland
quarter every 12 hours for 10 days. Concentrations of
ceftiofur and its metabolites in each milk sample
were determined to assess the rate of ceftiofur elimination.
Results—Although there were considerable variations
among mammary gland quarters and individual
cows, ceftiofur concentrations in milk from all treated
mammary gland quarters were less than the tolerance
(0.1 µg/mL) set by the FDA by 168 hours (7 days)
after the last intramammary administration of ceftiofur.
No drug concentrations were detected in milk
samples beyond this period. Ceftiofur was not detected
in any milk samples from nontreated mammary
gland quarters throughout the study.
Conclusions and Clinical Relevance—Ceftiofur
administered by the intramammary route as an extralabel
treatment for mastitis in dairy cows reaches
concentrations in milk greater than the tolerance set
by the FDA. Results indicated that milk from treated
mammary gland quarters should be discarded for a
minimum of 7 days after intramammary administration
of ceftiofur. Elimination of ceftiofur may be correlated
with milk production, and cows producing smaller
volumes of milk may have prolonged withdrawal
times. (J Am Vet Med Assoc 2004;224:1827–1830)