TOXICOLOGICAL EVALUATION AND DISPOSITION OF DV-7751A, A NEW QUINOLONEANTIMICROBIAL AGENT, ADMINISTERED ORALLY TO DOGS AND MONKEYS

We examined the toxic potentials and disposition of DV-7751a administe red repeatedly to immature beagle dogs and mature cynomolgus monkeys, Ln immature dogs (n = 3) orally given DV-7751a at 5, 10 and 15 mg/kg f or 8 days, arthropathy in the femur of a dog receiving 15 mg/kg was ob served at termination, but not at the lower doses, Serum concentration s at 2-6 h after the 7-day treatment were 0.8-1.5, 1.2-2.1 and 1.0-2.9 mu g/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 effe cts were found except for mild diarrhea throughout the experiment, Ser um concentrations at 2 to 4h after the final treatment were 8.3 to 11. 4 mu g/ml. In both species, there were no significant differences in t he serum drug concentration between the first and last (repeated) admi nistration, indicating no drug accumulation. In monkeys, hydrolysis of the urine sample showed no effect on the concentration of DV-7751a, w hereas that of the bile sample displayed a significant increase in its concentration, demonstrating that conjugated forms may be secreted in to bile, This was confirmed by a thin-layer chromatogram-bioautogram, and at least two kinds of active metabolites including a polar substan ce seemed to exist in bile, These results raise the possibility that D V-7751a possesses joint toxicity, but dose not show any effect on the hepatic function under conditions of this study.