EFFECTS OF QUINOLONES, MAGNESIUM-DEFICIENCY OR ZINC-DEFICIENCY ON JOINT CARTILAGE IN RATS

Quinolones are important antibacterial drugs which exhibit bactericida l activity against a broad spectrum of bacteria and possess favourable pharmacokinetics, such as good bioavailibilty after oral administrati on and a high volume of distribution. All drugs of this class are chon drotoxic in juvenile animals and thus contraindicated in children and adolescents as well as in pregnant and lactating women. After quinolon e treatment joint cartilage lesions have been observed in immature ani mals of various species which are characterized by alterations such as cleft formation and loss of chondrocytes. We have shown that identica l lesions can be induced in juvenile rats by feeding a magnesium-defic ient diet. As all quinolones known so far form chelate complexes with magnesium and other di- or trivalent cations. it is reasonable to assu me that the primary event for quinolone-induced arthropathy is a compl exation of magnesium by quinolones after their accumulation in cartila ge. The main results of our extensive studies on this topic in rats ar e summarized in this review. In addition, some new, so far unpublished results from our laboratories are presented. Single oral doses of 600 mg ofloxacin or fleroxacin/kg b wt are chondrotoxic in 5-week-old rat s. A five-day treatment with lower doses (2 x 100 mg ofloxacin/kg b wt daily) also induced cartilage lesions. Under these conditions plasma levels of the drug were below 10 mg/l and thus in the same range as pl asma levels under therapeutic conditions. Ciprofloxacin and sparfloxac in were not chondrotoxic under these conditions. However, as ciproflox acin was chondrotoxic after s.c.-injection, the lack of chondrotoxicit y after gastric intubation was probably due to the poor bioavailabilty of the drug in rats. By feeding a magnesium-deficient diet to juvenil e rats for 9 to 15 days, cartilage lesions could be induced which were identical to quinolone-induced lesions. We studied the alterations by light microscopy (staining with toluidine blue), immunohistochemistry (antibodies against matrix components and integrins on the cells), an d by electron microscopy. By all methods we found that the lesions ind uced by quinolones or by magnesium deficiency were not distinguishable .