title: Chondrotoxicity and toxicokinetics of novel quinolone antibacterial agents DC-159a and DX-619 in juvenile rats.
abstract: Quinolone antibacterial agents are extensively utilized in antimicrobial chemotherapy. However, they have been reported to induce arthropathy in juvenile animals, and the mechanism has not been clarified. Recently, we have demonstrated that Dusp1, Tnfrsf12a, Ptgs2, Fos, Mt1a, Plaur, Mmp3, Sstr1 and Has2 genes change in the articular cartilage of juvenile rats with a single oral administration of ofloxacin (OFLX), suggesting that these genes are involved in the induction of OFLX-induced chondrotoxicity. In the present study, to compare the chondrotoxic potential between new synthesized quinolones DC-159a and DX-619, and OFLX, they were orally administered by gavage at a dose level of 300 or 900 mg/kg/day to male juvenile Sprague-Dawley (SD) rats, 3 weeks of age, for 7 days. Then the distal humerus and femur were subjected to microscopic examination. Moreover, concentrations of these quinolones in the femoral articular cartilage were measured in male juvenile SD rats following a single oral administration at 100, 300 or 900 mg/kg. Furthermore, gene expression of Dusp1, Tnfrsf12a, Ptgs2, Fos, Mt1a, Plaur, Mmp3, Sstr1 and Has2 was investigated in the articular cartilage of the distal femur in male juvenile SD rats treated with 900 mg/kg of DC-159a or DX-619 by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) analysis. In a microscopic examination, no changes in the articular cartilage were observed in any animal administered DC-159a or DX-619. On the contrary, cavity formation and chondrocyte cluster in the cartilage of distal humerus and femur were noted in animals receiving OFLX at 300 mg/kg/day or more. In toxicokinetic analysis, the maximum concentration (C(max)) value in the articular cartilage (cartilage C(max)) of DC-159a or DX-619 at 900 mg/kg was lower than that of OFLX at 300 mg/kg. However, the area under the cartilage concentration-time curve (cartilage AUC)(0-24h) value of DC-159a or DX-619 at 900 mg/kg was higher than that of OFLX at 300 mg/kg. In qRT-PCR analysis, up-regulated Dusp1, Fos and Mt1a, and down-regulated Sstr1 and Has2 genes were seen in the femoral articular cartilage of rats given DX-619 or DC-159a at 900 mg/kg. However, Tnfrsf12a, Ptgs2, Plaur and Mmp3 genes, which were up-regulated in the distal femoral articular cartilage exposed to OFLX, did not increase or slightly increased. In conclusion, the penetration of DC-159a or DX-619 into the cartilage was low compared with that of OFLX, and no obvious changes in Tnfrsf12a, Ptgs2, Plaur and Mmp3 genes were observed in the articular cartilage of juvenile rats treated with DC-159a or DX-619, which was likely to be responsible for non-chondrotoxic potentials of DC-159a and DX-619.
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co. LTD., Edogawa-ku, Tokyo, Japan. goto.koichi.s7@daiichisankyo.co.jp
authors.forename: Koichi
authors.initials: K
authors.lastname: Goto
authors.forename: Koichi
authors.initials: K
authors.lastname: Yabe
authors.forename: Takami
authors.initials: T
authors.lastname: Suzuki
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Jindo
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbuissho
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D019540:Area Under Curve; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D015242:Ofloxacin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution
chemical_list: C530475:7-(7-amino-7-methyl-5-azaspiro(2.4)heptan-5-yl)-6-fluoro-1-(2-fluoro-1-cyclopropyl)-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid; D000631:Aminopyridines; D000900:Anti-Bacterial Agents; C505440:DX 619; D024841:Fluoroquinolones; D011759:Pyrrolidines; D015363:Quinolones; D015242:Ofloxacin