Toxicity and tissue residue depletion of levamisole hydrochloride in young goats

J. G. Babish From the Department of Pharmacology, New York State College of Veterinary Medicine (Babish), and the Toxic Chemicals Laboratory, New York State College of Agriculture and Life Sciences (Gutenmann, Lisk), Cornell University, Ithaca, NY 14853, and the Department of Veterinary and Animal Science, University of Massachusetts, Amherst, MA 01003.

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G. C. Coles From the Department of Pharmacology, New York State College of Veterinary Medicine (Babish), and the Toxic Chemicals Laboratory, New York State College of Agriculture and Life Sciences (Gutenmann, Lisk), Cornell University, Ithaca, NY 14853, and the Department of Veterinary and Animal Science, University of Massachusetts, Amherst, MA 01003.

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J. P. Tritschler II From the Department of Pharmacology, New York State College of Veterinary Medicine (Babish), and the Toxic Chemicals Laboratory, New York State College of Agriculture and Life Sciences (Gutenmann, Lisk), Cornell University, Ithaca, NY 14853, and the Department of Veterinary and Animal Science, University of Massachusetts, Amherst, MA 01003.

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W. H. Gutenmann From the Department of Pharmacology, New York State College of Veterinary Medicine (Babish), and the Toxic Chemicals Laboratory, New York State College of Agriculture and Life Sciences (Gutenmann, Lisk), Cornell University, Ithaca, NY 14853, and the Department of Veterinary and Animal Science, University of Massachusetts, Amherst, MA 01003.

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D. J. Lisk From the Department of Pharmacology, New York State College of Veterinary Medicine (Babish), and the Toxic Chemicals Laboratory, New York State College of Agriculture and Life Sciences (Gutenmann, Lisk), Cornell University, Ithaca, NY 14853, and the Department of Veterinary and Animal Science, University of Massachusetts, Amherst, MA 01003.

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SUMMARY

Toxicity and tissue residue depletion studies were conducted in young goats, using an oral drench formulation of levamisole hydrochloride. In the target animal toxicity study, 3 groups of 5 goats each were given levamisole orally to provide approximately 11.88, 23.76, or 35.64 mg of levamisole HCl/kg/d for 3 consecutive days; a fourth group of 5 goats served as untreated controls. Blood samples were taken for analysis of levamisole 1 day prior to dosing and 1, 2, 3, 4, and 7 days following the third dose. At the 35.64-mg/kg dose, 2 of 5 goats responded with typical cholinergic signs of toxicosis on each of the 3 days of dosing. The times for the onset of clinical signs of toxicosis ranged from 18 to 63 minutes, with an average duration of 32 minutes. Administration of 23.76 mg of levamisole HCl/kg resulted in hyperactive behavior in 1 of 5 goats only on the first day of dosing; no abnormal behavior was observed in any of the 5 goats following the second or third dose of levamisole HCl at 23.76 mg/kg. Untoward effects were not seen in the 5 goats dosed at 11.88 mg of levamisole HCl/kg or in the controls during the 3-day dosing period or in the following 7-day observation period. Overall, the observed signs of toxicosis did not become more severe, affect more goats, or persist for a longer period on subsequent dosing days.

In the 35.64-mg/kg/d group of the toxicity study, parent drug was detected in the serum of all 4 goats for which assaying was done 1 day after dosing and in the serum of 1 of the 4 goats for which assay was done 2 days after dosing. Only 1 of the 3 goats given 23.67 mg of levamisole HCl/kg/d had a detectable serum concentration of levamisole 1 day after dosing, and none of the goats had detectable serum levamisole concentrations 2 days after the final dose was given. One of the 3 goats for which assaying followed dosing of 11.88 mg/kg/d had measurable levamisole serum concentrations that persisted for 4 days after dosing; the apparent serum half-life of elimination for levamisole in this goat was 19.4 hours. Serum concentrations of levamisole at 1 day after dosing did not correlate with signs of toxicosis in goats immediately following dosing.

Liver, kidney, and muscle samples from 25 goats given a single oral dose of 11.88 mg levamisole HCl/kg were analyzed for drug residues 1, 2, 3, 4, and 7 days after dosing (5 goats/sampling time). Within goats, the highest concentrations of levamisole were found in the liver, followed by kidney and then muscle. Depletion of levamisole from the liver was modeled as a single exponential decay function; using means, or an estimate of the 95th percentile of the population, from days 1, 2, 3, and 4 after dosing resulted in values for apparent half-lives of elimination of 1.4 and 1.2 days, respectively. Adjusting the means and 95th percentile estimates by eliminating observations > 3 sd from the mean had little effect on the apparent half-lives of elimination (1.3 and 1.6 days), although the degree of fit was improved 17 and 28%, respectively. Fitting of the outlier values of levamisole liver concentrations to a similar monoexponential equation resulted in an estimate of the apparent half-life of elimination of 2.4 days. Levamisole concentrations in kidney and muscle decreased too rapidly to model their elimination rates.

On the basis of serum kinetics of levamisole in 1 goat (of 10) for which the serum was assayed and liver depletion rates of levamisole estimated from 8 (of 25) goats, we concluded that goats may possess a genetic polymorphism with respect to levamisole metabolism and could be considered either normal or slow eliminators. Regardless of levamisole phenotype, however, liver residues of levamisole were estimated to be < 100 μg/kg for 9 days following a single, oral dose of 11.88 mg of levamisole HCl/kg.

SUMMARY

Toxicity and tissue residue depletion studies were conducted in young goats, using an oral drench formulation of levamisole hydrochloride. In the target animal toxicity study, 3 groups of 5 goats each were given levamisole orally to provide approximately 11.88, 23.76, or 35.64 mg of levamisole HCl/kg/d for 3 consecutive days; a fourth group of 5 goats served as untreated controls. Blood samples were taken for analysis of levamisole 1 day prior to dosing and 1, 2, 3, 4, and 7 days following the third dose. At the 35.64-mg/kg dose, 2 of 5 goats responded with typical cholinergic signs of toxicosis on each of the 3 days of dosing. The times for the onset of clinical signs of toxicosis ranged from 18 to 63 minutes, with an average duration of 32 minutes. Administration of 23.76 mg of levamisole HCl/kg resulted in hyperactive behavior in 1 of 5 goats only on the first day of dosing; no abnormal behavior was observed in any of the 5 goats following the second or third dose of levamisole HCl at 23.76 mg/kg. Untoward effects were not seen in the 5 goats dosed at 11.88 mg of levamisole HCl/kg or in the controls during the 3-day dosing period or in the following 7-day observation period. Overall, the observed signs of toxicosis did not become more severe, affect more goats, or persist for a longer period on subsequent dosing days.

In the 35.64-mg/kg/d group of the toxicity study, parent drug was detected in the serum of all 4 goats for which assaying was done 1 day after dosing and in the serum of 1 of the 4 goats for which assay was done 2 days after dosing. Only 1 of the 3 goats given 23.67 mg of levamisole HCl/kg/d had a detectable serum concentration of levamisole 1 day after dosing, and none of the goats had detectable serum levamisole concentrations 2 days after the final dose was given. One of the 3 goats for which assaying followed dosing of 11.88 mg/kg/d had measurable levamisole serum concentrations that persisted for 4 days after dosing; the apparent serum half-life of elimination for levamisole in this goat was 19.4 hours. Serum concentrations of levamisole at 1 day after dosing did not correlate with signs of toxicosis in goats immediately following dosing.

Liver, kidney, and muscle samples from 25 goats given a single oral dose of 11.88 mg levamisole HCl/kg were analyzed for drug residues 1, 2, 3, 4, and 7 days after dosing (5 goats/sampling time). Within goats, the highest concentrations of levamisole were found in the liver, followed by kidney and then muscle. Depletion of levamisole from the liver was modeled as a single exponential decay function; using means, or an estimate of the 95th percentile of the population, from days 1, 2, 3, and 4 after dosing resulted in values for apparent half-lives of elimination of 1.4 and 1.2 days, respectively. Adjusting the means and 95th percentile estimates by eliminating observations > 3 sd from the mean had little effect on the apparent half-lives of elimination (1.3 and 1.6 days), although the degree of fit was improved 17 and 28%, respectively. Fitting of the outlier values of levamisole liver concentrations to a similar monoexponential equation resulted in an estimate of the apparent half-life of elimination of 2.4 days. Levamisole concentrations in kidney and muscle decreased too rapidly to model their elimination rates.

On the basis of serum kinetics of levamisole in 1 goat (of 10) for which the serum was assayed and liver depletion rates of levamisole estimated from 8 (of 25) goats, we concluded that goats may possess a genetic polymorphism with respect to levamisole metabolism and could be considered either normal or slow eliminators. Regardless of levamisole phenotype, however, liver residues of levamisole were estimated to be < 100 μg/kg for 9 days following a single, oral dose of 11.88 mg of levamisole HCl/kg.

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