R. Stahlmann et al., EFFECTS OF QUINOLONES, MAGNESIUM-DEFICIENCY OR ZINC-DEFICIENCY ON JOINT CARTILAGE IN RATS, Magnesium-Bulletin, 19(1), 1997, pp. 7-22
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 In addition, some new, so far unpublished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
.