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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 determine the pharmacokinetics of florfenicol, terbinafine, and betamethasone acetate after topical application to canine auricular skin and the influence of synthetic canine cerumen on pharmacokinetics.

SAMPLE Auricular skin from 6 euthanized shelter dogs (3 females and 3 neutered males with no visible signs of otitis externa).

PROCEDURES Skin adjacent to the external opening of the ear canal was collected and prepared for use in a 2-compartment flow-through diffusion cell system to evaluate penetration of an otic gel containing florfenicol, terbinafine, and betamethasone acetate over a 24-hour period. Radiolabeled 14C-terbinafine hydrochloride and 3H-betamethasone acetate were added to the gel to determine dermal penetration and distribution. Florfenicol absorption was determined by use of high-performance liquid chromatography–UV detection. Additionally, the effect of synthetic canine cerumen on the pharmacokinetics of all compounds was evaluated.

RESULTS During the 24-hour experiment, mean ± SD percentage absorption without the presence of synthetic canine cerumen was 0.28 ± 0.09% for 3H-betamethasone acetate, 0.06 ± 0.06% for florfenicol, and 0.06 ± 0.02% for 14C-terbinafine hydrochloride. Absorption profiles revealed no impact of synthetic canine cerumen on skin absorption for all 3 active compounds in the gel or on skin distribution of 3H-betamethasone acetate and 14C-terbinafine hydrochloride.

CONCLUSIONS AND CLINICAL RELEVANCE 3H-betamethasone acetate, 14C-terbinafine hydrochloride, and florfenicol were all absorbed in vitro through healthy auricular skin specimens within the first 24 hours after topical application. Synthetic canine cerumen had no impact on dermal absorption in vitro, but it may serve as a temporary reservoir that prolongs the release of topical drugs.

Full 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 develop a flow-limited, physiologicbased pharmacokinetic model for use in estimating concentrations of sulfamethazine after IV administration to swine.

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 (FARAD).

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)

Full access
in American Journal of Veterinary Research
in Journal of the American Veterinary Medical Association

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 determine elimination kinetics of tilmicosin in milk following intramammary administration in lactating dairy cattle.

Design—Prospective pharmacokinetic study.

Animals—6 lactating dairy cows.

Procedures—Following collection of baseline milk samples, 1,200 mg (4 mL) of tilmicosin was infused into the left front and right rear mammary glands of each cow. Approximately 12 hours later, an additional 1,200 mg of tilmicosin was infused into the left front and right rear glands after milking. Milk samples were then collected from each gland at milking time for 40 days. Concentration of tilmicosin was determined by means of ultraperformance liquid chromatography–mass spectrometry, and a milk withdrawal interval for tilmicosin was calculated on the basis of the tolerance limit method.

Results—Although there was considerable variation between glands, concentration of tilmicosin was high in milk from treated glands and had a long half-life in treated and untreated glands. Tilmicosin was detected in all treated glands for the entire 40-day study period and was detected in untreated glands for approximately 30 to 35 days.

Conclusions and Clinical Relevance—Findings indicated that tilmicosin should not be administered by the intramammary route in lactating dairy cows. Milk from all glands of any cows accidentally treated should be discarded for a minimum of 82 days following intramammary administration.

Full access
in Journal of the American Veterinary Medical Association
in Journal of the American Veterinary Medical Association
in Journal of the American Veterinary Medical Association