title: Toxicological evaluation and disposition of DV-7751a, a new quinolone antimicrobial agent, administered orally to dogs and monkeys.
abstract: We examined the toxic potentials and disposition of DV-7751a administered repeatedly to immature beagle dogs and mature cynomolgus monkeys. In immature dogs (n = 3) orally given DV-7751a at 5, 10 and 15 mg/kg for 8 days, arthropathy in the femur of a dog receiving 15 mg/kg was observed at termination, but not at the lower doses. Serum concentrations at 2-6 h after the 7-day treatment were 0.8-1.5, 1.2-2.1 and 1.0-2.9 micrograms/ml at 5, 10 and 15 mg/kg, respectively. In mature monkeys (n = 3) treated orally with DV-7751a at 100 mg/kg for 14 days, no toxic effects were found except for mild diarrhea throughout the experiment. Serum concentrations at 2 to 4 h after the final treatment were 8.3 to 11.4 micrograms/ml. In both species, there were no significant differences in the serum drug concentration between the first and last (repeated) administration, indicating no drug accumulation. In monkeys, hydrolysis of the urine sample showed no effect on the concentration of DV-7751a, whereas that of the bile sample displayed a significant increase in its concentration, demonstrating that conjugated forms may be secreted into bile. This was confirmed by a thin-layer chromatogram-bioautogram, and at least two kinds of active metabolites including a polar substance seemed to exist in bile. These results raise the possibility that DV-7751a possesses joint toxicity, but dose not show any effect on the hepatic function under conditions of this study.
authors.affiliation: New Product Research Laboratories I, Daiichi Pharmaceutical Co., Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
authors.forename: K
authors.initials: K
authors.lastname: Matsubayashi
authors.forename: M
authors.initials: M
authors.lastname: Sekiguchi
authors.forename: I
authors.initials: I
authors.lastname: Hayakawa
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000633:toxicity*; D004285:Dogs; D005260:Female; D005269:Femur / Q000187:drug effects / Q000473:pathology; D024841:Fluoroquinolones; D007596:Joints / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008252:Macaca fascicularis; D008297:Male; D015363:Quinolones / Q000633:toxicity*
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D015363:Quinolones; C084755:DV 7751a