Effects of moxifloxacin and clinafloxacin on murine limb buds cultured in regular and in magnesium-deficient medium.
Evaluation of the prenatal toxicity of a substance in rats or other animals according to the current guidelines is often hampered by the rapid metabolism of the test compound and/or by maternal toxicity. One example for such a compound is moxifloxacin. In vitro systems offer the possibility to study the direct effects of the test compound on embryonic tissues. The aim of this study was to evaluate the embryotoxic potential of moxifloxacin in vitro using the murine limb bud culture. Clinafloxacin, which was found to be teratogenic when tested in rats, was used for comparison. The effects of various concentrations of moxifloxacin (10, 30, 60 and 100 mg/L) and clinafloxacin (3, 10 and 30 mg/L) on growth and differentiation of 12-day-old murine limb buds were studied in a standard and in a magnesium-deficient medium. After termination of the culture, the respective front limb buds were examined by different methods. Clinafloxacin showed clear-cut effects at a concentration of 30 mg/L in both media. Effects were similarly pronounced as the effects observed with moxifloxacin at a concentration of 100 mg/L. Lower concentrations of moxifloxacin, which are achieved during therapy in humans, did not impair growth and differentiation of limb buds. Using electron microscopy, slight ultrastructural changes could be seen after exposure to 3 mg clinafloxacin/L medium. Ultrastructurally, clinafloxacin caused a concentration-dependent decrease of the extracellular matrix, swelling of cell organelles and at higher concentrations necrotic chondrocytes. These effects were significantly enhanced in a magnesium-deficient medium. In conclusion, the effects of moxifloxacin on murine limb buds in vitro were definitely less pronounced than those of clinafloxacin. Effects on growth and differentiation occurred with moxifloxacin only at concentrations that are higher than plasma concentrations observed during therapy. This result is of special interest, because due to rapid metabolism of moxifloxacin in rats results from a routinely performed segment II type study cannot be used for a risk assessment.
Bode
Kerstin
K
Federal Office of Consumer Protection and Food Safety, Mauerstr. 39-42, 10117 Berlin, Germany.
Kunz
Andrea
A
Baumann-Wilschke
Irmela
I
Shakibaei
Mehdi
M
Stahlmann
Ralf
R
D000818:Animals; D000890:Anti-Infective Agents / Q000633:toxicity*; D001372:Aza Compounds / Q000633:toxicity*; D046149:Embryo Culture Techniques; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000196:embryology; D024841:Fluoroquinolones / Q000633:toxicity*; D018878:Limb Buds / Q000187:drug effects* / Q000196:embryology; D008274:Magnesium / Q000494:pharmacology; D051379:Mice; D009024:Morphogenesis / Q000187:drug effects; D000077266:Moxifloxacin; D011804:Quinolines / Q000633:toxicity*
D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; C057477:clinafloxacin; D008274:Magnesium; D000077266:Moxifloxacin