Pharmacokinetics of cyadox and its main metabolites in rats, pigs, chickens, and carps following oral administration at three dosage.

Cyadox (CYA), a 1,4-dioxide quinoxaline, is a safe and effective antibacterial agent with potential use in food-producing animals. The aim of this study was to compare the pharmacokinetics of CYA (Cy0) and its main metabolites [bisdeoxycyadox (Cy1), 4-desoxycyadox (Cy2), N-(quinoxaline-2-methyl)-cyanide acetyl hydrazine (Cy4), quinoxaline-2-carboxylic acid (Cy6), and 2-hydromethyl-3-hydroxy-quinoxaline (Cy12)] after oral administration at three dosages in pigs, chickens, carps, and rats. The concentration vs. time profile in plasma after single oral administration indicated that CYA was rapidly dissociated into its metabolites and showed the widest distribution in all animals, with the highest apparent volume of distribution. Cy0 and Cy6 persisted for the longest time at lower concentration. Cy1and Cy4 concentration was the highest in pig and rat plasma, while Cy1 was undetectable in chickens, and Cy4 was undetectable in carps following administration at three dosages. Different dosage of the CYX and its metabolites had no significant effect on wash-out period. This study revealed obvious species-specific differences in the kinetic behavior of CYA and its metabolites, which may be related to clinical efficacy and toxicity. Our results would facilitate the judicious use of CYA in different animals.

Synthesis of tritium-labeled cyadox, a promising antimicrobial growth-promoting agent with high specific activity.

Cyadox is a new antimicrobial growth-promoting agent for food-producing animals. Studies on radiolabeled compounds enable the use of sensitive radiometric analytical methods and help in the elucidation of metabolic and elimination pathways. In the present study, 6-[3H]-cyadox with a high specific activity of 2.08 Ci/mmol was prepared by the catalytic bromine-tritium exchange of 4-bromo-2-nitroaniline followed by a three-step microscale synthesis, giving a high yield between 36.16% and 94.75%.

Metabolic Disposition and Elimination of Cyadox in Pigs, Chickens, Carp, and Rats.

The metabolism, distribution, and elimination of cyadox (CYA) is investigated in pigs, chickens, carp, and rats to identify the marker residue and target tissue of CYA in food animals for food safety concerns. Following a single oral gavage of [(3)H]-CYA, the total radioactivity was rapidly excreted, with more than 95% of the dose excreted within 14 days in the four species. Fecal excretion of the total radioactivity was 66.2% and 51.6%, and urinary excretion of the total radioactivity was 28.35% and 44.3% in rats and pigs, respectively. Radioactivity was observed in nearly all of the tissues in the first 6 h after 7 days of consecutive oral dosing. The highest radioactivity and longest persistence were in the livers and kidneys, where the majority of the radioactivity was cleared within 7 days. A total of 15 metabolites were identified in rats, pigs, chickens, and carp, and eight new metabolites were identified for the first time in vivo. No parent drug could be detected in the tissues of rats and pigs. The major metabolites of CYA were Cy1, Cy3, and Cy6 in pigs, Cy1, Cy5, and Cy6 in chickens, Cy1, Cy2, and Cy4 in carp, and Cy1, Cy2, Cy4, and Cy5 in rats. Cy1 was suggested to be the marker residue, and the kidneys were identified as the target tissue of CYA in pigs and chickens. These results provide comprehensive information for the food safety evaluation of CYA in food animals and will improve the understanding of the pharmacology and toxicology of CYA in animals.