Chondrotoxicity of ciprofloxacin in immature Beagle dogs: immunohistochemistry, electron microscopy and drug plasma concentrations

The systemic effects of ciprofloxacin in immature Beagles were studied. Dog s of 10-11 weeks were dosed orally for 5 days with 0 (n = 3), 30 (n = 5) an d 200 (n = 5) mg ciprofloxacin/kg body wt. Plasma concentrations were measu red by high-performance liquid chromatography (HPLC) 1 h after dosing (assu ming to be peak concentrations). In view of the high doses used, the plasma concentrations were rather low and declined during the study period. For e xample, plasma concentrations in the high dose group were 6.6 +/- 0.9 mg/l (day 1), 3.9 +/- 1.4 mg/l (day 3), and 2.6 +/- 1.6 mg/l (day 5). In control dogs and in dogs treated with the low dose of ciprofloxacin no pathologica l changes were seen by light microscopy, However, cleft formation and erosi ons were observed in joint cartilage from two of five dogs treated with 200 mg/kg. It is noteworthy that despite the high dose used cartilage lesions were not detectable in all five dogs of this group by light microscopy. Usi ng antibodies against cell membrane receptors (e.g. the alpha(5)beta(1)-int egrin) or matrix components (fibronectin, collagen II) the articular cartil age effects were studied in detail by immunohistochemistry. The most sensit ive alteration was an increase in fibronectin which was detectable in the v icinity of the lesions in cartilage samples from the group of dogs administ ered the high dose. No clear-cut changes were seen with the use of antibodi es against other matrix components. Electron microscopy revealed typical al terations in chondrocytes from dogs treated with ciprofloxacin: e.g., swoll en mitochondria and enlarged rough endoplasmic reticulum. These changes wer e much more pronounced in dogs from the high dose group than in dogs from t he low dose group. Our main conclusion is that after oral administration ci profloxacin exhibits rather low chondrotoxicity, even in the most sensitive species known to date. This correlates with the findings in humans that ci profloxacin seems to be less chondrotoxic than pefloxacin or other quinolon es.