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Submitted to: Xenobiotica
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 3/7/1996 Publication Date: N/A Citation: N/A Interpretive Summary: Levamisole is an anthelmintic approved for use in sheep, swine, and cattle (but not lactating cows) to control stomach and intestinal worms. Because levamisole is readily available there is concern that it may be used in lactating cows resulting in residues in milk and/or tissues. Studies on the disposition of levamisole conducted at other laboratories have not used radiotracer methodology and only the parent drug was monitored in milk and tissues. The studies reported here were conducted with 14C-labeled levamisole to make it possible to monitor all levamisole related residues (parent compound and metabolites) in milk, tissues, and excreta. These studies have demonstrated that: (1) the disposition of 14C in the lactating cow was very similar after oral and subcutaneous administration of 14C-levamisole; (2) less than 1% of the 14C was secreted in milk collected from 0-48 hours after dosing with 14C-levamisole; (3) the parent compound 14C-levamisole accounted for 12% or less (declined with time after dosing) of the total 14C-activity in milk; (4) most of the 14C-activity given as 14C-levamisole was secreted in the urine but no parent compound was detected in the urine; (5) less than 5% of the administered 14C-activity remained in the animals 48 hours after dosing with 14C-levamisole and the liver was the tissue with the highest 14C- residues; (6) less than 5% of the total 14C-residues in the liver was present as 14C-levamisole; (7) the major 14C-labeled metabolites in urine and milk resulted from oxidation of levamisole. This information will be of value to regulatory agencies as they decide what compound (marker compound) to monitor as an indicator of levamisole related residues in milk and tissues. Technical Abstract: 14C-Levamisole {l(-)-2,3,5,6-tetrahydro-6-phenyl[U-14C]imidazo[2,1-b]- thiazole} was administered orally and subcutaneously to lactating cows (8 mg/kg body weight). Urine, faeces, milk and blood samples were collected from 0-48 h after dosing and tissues were collected 48 h after dosing. 14C-Labeled residues (ppm 14C-levamisole equivalents) in blood were highest at 3 h (2.2 ppm, oral dose) or 6 h (2.1 ppm, subcutaneous dose) and then declined to less than 0.5 ppm 48 h after dosing. 14C-Labeled residues in milk were highest in samples collected from 0-12 h after dosing (1.55 ppm and 1.86 ppm of levamisole equivalents, respectively, from oral and subcutaneously dosed animals) and declined to 0.06 ppm in milk collected from 36-48 h after dosing. The parent compound, 14C-levamisole, accounted for 12% or less (declined with time after dosing) of the total 14C in the milk. Three 14C-labeled metabolites (formed by oxidation of the imidazoline ring and/or opening of thiazolidine ring) in milk were isolated and identified. Urine excretion accounted for 83% and 84% and faecal excretion accounted for 11 and 9% of the total 14C given orally and subcutaneously, respectively, as 14C-levamisole. No 14C- levamisole was detected in the urine; the major urinary metabolite (formed by opening of thiazolidine ring) was isolated and identified. The 14C remaining in the animals 48 h after dosing was widely distributed in body tissues; however, the concentration in the liver was substantially higher than in all other tissues examined. Less than 5% of the 14C in the liver was present as 14C-levamisole. |
