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SUMMARY

Objectives

To assess the influence of solvent plus various mixtures on percutaneous absorption and disposition of the carbamate insecticide, carbaryl (CA).

Animals

Skin was obtained from the dorsum of 14 female weanling specific-pathogen-free Yorkshire pigs.

Procedure

In this 8-hour in vitro flow-through diffusion study, porcine skin sections were dosed with 40 μg of CA/cm2 of surface area, different amounts of solvents (40 or 80% acetone or dimethyl sulfoxide [DMSO]), different amounts of a surfactant (0, 1, or 5% sodium lauryl sulfate [SLS]), an insect repellent (0 or 15% diethyl-m-toluamide [DEET]), an insecticide synergist (0 or 2% piperonyl butoxide [PB]), and a CA metabolite (40 μg/cm2 1-naphthol (1-NA]).

Results

In general, CA absorption was greater from acetone than from DMSO mixtures, and CA penetration into skin and stratum corneum was greater from DMSO at 8 hours. This is consistent with the flux-time profiles, which depicted initial peak flux within 2 to 3 hours for most acetone mixtures, but a slow increase in flux for DMSO mixtures. Irrespective of the solvent, increasing water content in pesticide dosing mixtures significantly increased CA absorption from SLS mixtures only. The SLS also enhanced CA absorption, especially at low solvent concentrations. The DEET significantly reduced CA absorption from acetone, but not from DMSO mixtures, and 1-NA enhanced CA absorption from acetone, but not from DMSO mixtures. Piperonyl butoxide significantly enhanced CA absorption from acetone and DMSO mixtures. However, addition of PB or PB plus SLS did not significantly increase CA flux above that observed from solvent plus surfactant mixtures.

Conclusions

Inert ingredients can modulate percutaneous absorption of toxicologically important pesticides and their effect or activity on CA disposition is dependent on solvent specificity and solvent concentration. Whereas SLS, PB, and 1-NA can enhance pesticide absorption, DEET can reduce absorption. (Am J Vet Res 1998;59:168–175)

Free access
in American Journal of Veterinary Research

Abstract

Objective

To develop and validate a population pharmacokinetic model for gentamicin in horses, using retrospective clinical data.

Animals

62 horses that had been treated IV with multiple doses of gentamicin at our veterinary teaching hospital between 1987 and 1996.

Procedure

46 horses were assigned to the study group, and 16 to the validation group. Detailed history of dosage, sample collection times, and selected pathophysiologic variables were recorded for each patient. Samples were analyzed by use of a fluorescence polarization immunoassay method. Pharm-acostatistical analysis was conducted, using computer software. The predictive model correlates pharmacokinetic parameters to concomitant pathophysiologic variables and estimates the inter- and intraindividual variability in disposition.

Results

A two-compartment model best described the data. Clearance (Cl) was linearly correlated to body weight and serum creatinine concentration. Volume of the central compartment (Vdc) was linearly related to body weight. Interindividual coefficients of variability for Cl and Vdc were 24 and 16%, respectively. The residual variability (intraindividual) was 13%; mean prediction error percent (bias) was 2%; and mean absolute prediction error percent (precision) was 29%.

Conclusions

Population pharmacokinetic analysis allows study of the basic features of gentamicin disposition in horses with sparse data per individual. A considerable proportion of the pharmacokinetic variability of gentamicin in our study population was explained by differences in body weight and serum creatinine concentration.

Clinical Relevance

Population pharmacokinetics can be used to design first-dosage regimens according to the clinical characteristics of individual animals. Population pharmacokinetic models could also be included in Bayesian forecasting strategies to improve plasma concentration predictions in individual patients. (Am J Vet Res 1998;59:1589-1598)

Free access
in American Journal of Veterinary Research

Abstract

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.

Full access
in American Journal of Veterinary Research

Abstract

Objective—To determine the tissue depletion profile of tulathromycin and determine an appropriate slaughter withdrawal interval in meat goats after multiple SC injections of the drug.

Animals—16 healthy Boer goats.

Procedures—All goats were administered tulathromycin (2.5 mg/kg, SC) twice, with a 7-day interval between doses. Blood samples were collected throughout the study, and goats were euthanized at 2, 5, 10, and 20 days after the second tulathromycin dose. Lung, liver, kidney, fat, and muscle tissues were collected. Concentrations of tulathromycin in plasma and the hydrolytic tulathromycin fragment CP-60,300 in tissue samples were determined with ultrahigh-pressure liquid chromatography–tandem mass spectrometry.

Results—The plasma profile of tulathromycin was biphasic. Absorption was very rapid, with maximum drug concentrations (1.00 ± 0.42 μg/mL and 2.09 ± 1.77 μg/mL following the first and second doses, respectively) detected within approximately 1 hour after injection. Plasma terminal elimination half-life of tulathromycin was 61.4 ± 14.1 hours after the second dose. Half-lives in tissue ranged from 2.4 days for muscle to 9.0 days for lung tissue; kidney tissue was used to determine the withdrawal interval for tulathromycin in goats because it is considered an edible tissue.

Conclusions and Clinical Relevance—On the basis of the tissue tolerance limit in cattle of 5 ppm (μg/g), the calculated withdrawal interval for tulathromycin would be 19 days following SC administration in goats. On the basis of the more stringent guidelines recommended by the FDA, the calculated meat withdrawal interval following tulathromycin administration in goats was 34 days.

Full access
in American Journal of Veterinary Research

Abstract

OBJECTIVE To describe plasma pharmacokinetic parameters and tissue elimination of flunixin in veal calves.

ANIMALS 20 unweaned Holstein calves between 3 and 6 weeks old.

PROCEDURES Each calf received flunixin (2.2 mg/kg, IV, q 24 h) for 3 days. Blood samples were collected from all calves before the first dose and at predetermined times after the first and last doses. Beginning 24 hours after injection of the last dose, 4 calves were euthanized each day for 5 days. Plasma and tissue samples were analyzed by ultraperformance liquid chromatography. Pharmacokinetic parameters were calculated by compartmental and noncompartmental methods.

RESULTS Mean ± SD plasma flunixin elimination half-life, residence time, and clearance were 1.32 ± 0.94 hours, 12.54 ± 10.96 hours, and 64.6 ± 40.7 mL/h/kg, respectively. Mean hepatic and muscle flunixin concentrations decreased to below FDA-established tolerance limits (0.125 and 0.025 μg/mL, respectively) for adult cattle by 3 and 2 days, respectively, after injection of the last dose of flunixin. Detectable flunixin concentrations were present in both the liver and muscle for at least 5 days after injection of the last dose.

CONCLUSIONS AND CLINICAL RELEVANCE The labeled slaughter withdrawal interval for flunixin in adult cattle is 4 days. Because administration of flunixin to veal calves represents extralabel drug use, any detectable flunixin concentrations in edible tissues are considered a violation. Results indicated that a slaughter withdrawal interval of several weeks may be necessary to ensure that violative tissue residues of flunixin are not detected in veal calves treated with that drug.

Full access
in American Journal of Veterinary Research