Subacute Toxicity and Toxicokinetics of a New Antibiotic, DW-224a, after Single and 4-Week Repeated Oral Administration in Dogs

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  • Han Junghee
    Division of Toxicology and Toxicokinetics, Korea Institute of Toxicology, KRICT
  • Kim Jong-Choon
    Department of Pharmacology and Toxicology, College of Veterinary Medicine, Chonnam National University
  • Chung Moon-Koo
    Division of Toxicology and Toxicokinetics, Korea Institute of Toxicology, KRICT
  • Kim Byungbae
    College of Science and Technology, Hongik University
  • Choi Dong-Rack
    Dong Wha Pharm. Ind. Co., LTD

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The subacute toxicity and toxicokinetics of a new fluoroquinolone antibiotic, DW-224a, were evaluated after single (on the 1st day) and 4-week (on the 28th day) oral administration of the drug at doses of 0 (to serve as a control), 10, 30, and 90 mg/kg/d, to male and female dogs (n=3 for male and female dogs for each dose). During the test period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weight and histopathology were examined. The 4-week repeated oral dose of DW-224a resulted in vomiting, salivation, increased serum cholesterol level, and atrophy of thymus and testes. The target organ was determined to be the thymus and testes. The absolute toxic dose of DW-224a was 30 mg/kg and the level at which no adverse effects were observed was 10 mg/kg for both sexes. There were no significant gender differences in the pharmacokinetic parameters of DW-224a for each dose after both single and 4-week oral administration. The pharmacokinetic parameters of DW-224a were dose independent after a single oral administration; the time to reach the peak plasma concentration (Tmax) and the dose-normalized area under the plasma concentration–time curve from time zero to 24 h in plasma (AUC0—24 h) were not significantly different among the three doses. The accumulation of DW-224a after 4-week oral administration was not notable at the toxic dose of 90 mg/kg/d. For example, after 4-week administration, the dose-normalized AUC0—24 h value at 90 mg/kg/d (7.69, 7.05 μg h/ml) was not significantly greater than that at 10 mg/kg/d. After 4-week oral administration, the dose-normalized Cmax and AUC0—24 h at 90 mg/kg/d were not significantly higher and greater, respectively, than those after a single oral administration.

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