Children as a special population at risk--quinolones as an example for xenobiotics exhibiting skeletal toxicity

Abstract

The sensitivity of the immature skeletal system during postnatal mammalian development was discussed during the workshop "Children as a Sensitive Subgroup and their Role in Regulatory Toxicology" (Schwenk et al. 2002, Arch Toxicol, in press). As a typical example of xenobiotics exhibiting this extraordinary type of toxicity, the quinolone-induced effects on cartilage, bone growth, and tendons were considered in depth. Animal experiments indicate that chondrotoxicity of quinolones can affect articular cartilage depending on the developmental stage. Results from studies with pipemidic acid in dogs at various developmental stages from 1 week old to 17 months old showed pronounced effects in the most sensitive age groups: 3- to 6-month-old dogs exhibited gait alterations and lameness, but signs of toxicity were not observed in 12- or 17-month-old dogs. Similarly, experiments performed in rats indicate that they exhibit the highest sensitivity for articular cartilage defects at a certain stage of development between 3 and 6 weeks postnatally; mature articular cartilage does not seem to be a target for quinolone-induced toxicity. Some very limited data indicate that in animals at an early developmental phase the epiphyseal growth plate can also be damaged by quinolones, and that these effects are associated with irreversible bone damage and growth inhibition. Another manifestation of toxic effects of quinolones on connective tissue structures are tendopathies. For this effect, it is not quite clear whether juveniles are more susceptible than adults because clinical and experimental data seem to point in different directions. Pathogenesis of both effects can probably be explained by the magnesium-chelating properties of these drugs, leading to a deficit of functionally available magnesium and, subsequently, to radical formation and irreversible connective tissue lesions. However, unequivocal explanations for the phase-dependency of the effects are lacking.