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Antimicrobial Agents and Chemotherapy, June 2002, p. 1755-1759, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1755-1759.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Synergistic Effect of Ofloxacin and Magnesium Deficiency on Joint Cartilage in Immature Rats

Edith Lozo,¹ Kai Riecke,¹ Rudolf Schwabe,² Jürgen Vormann,³ and Ralf Stahlmann^1*

Institute of Clinical Pharmacology and Toxicology, Benjamin Franklin Medical Center, Freie Universität Berlin, 14195 Berlin,¹ MAK-BUA Gruppe Weihenstephan, 85350 Freising Weihenstephan,² Protina GmbH, 85737 Ismaning, Germany³

Received 13 August 2001/ Returned for modification 6 February 2002/ Accepted 27 February 2002

Single high oral doses of fluoroquinolones (e.g., 1,200 mg of ofloxacin/kg of body weight) are chondrotoxic in juvenile rats. Characteristic cartilage lesions are detectable as early as 12 h after treatment. Since this dosing regimen does not reflect the therapeutic situation, we studied the effects of a 5- or 7-day treatment with ofloxacin at lower oral doses (10, 30, and 100 mg/kg twice a day [b.i.d.]) on joint cartilage in 4-week-old rats. We additionally investigated whether the effects of ofloxacin under these conditions are enhanced in animals kept on a magnesium-deficient diet during treatment. Knee joints were examined histologically. The concentrations of ofloxacin and magnesium were determined in plasma and cartilage. The lowest ofloxacin dose at which cartilage lesions occurred in animals on a standard diet was 100 mg/kg b.i.d. for 5 days. Peak plasma ofloxacin levels were approximately 10 mg/liter in these rats and thus were in the same range as the levels in the plasma of humans during therapy with high doses of ofloxacin. Treatment with 30 mg of ofloxacin/kg b.i.d. for 7 days caused no cartilage lesions in rats on a standard diet, but lesions did occur in 10 of 12 rats that were simultaneously fed a magnesium-deficient diet. Magnesium concentrations in bone, plasma, and cartilage from animals on an Mg²⁺-deficient diet were significantly lower than those in the controls. The concentration in plasma from animals on an Mg²⁺-deficient diet was 0.27 ± 0.03 mmol/liter, whereas it was 0.88 ± 0.08 mmol/liter in plasma from rats on a standard diet (means ± standard deviations). Ofloxacin treatment did not change the total magnesium concentrations in tissues, as determined with ashed samples. The incidence of ofloxacin-induced lesions was higher in the magnesium-deficient animals, suggesting a synergistic effect. These results must be taken into account for a benefit-risk evaluation if ofloxacin is considered for use in the pediatric population.

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* Corresponding author. Mailing address: Institut für Klinische Pharmakologie und Toxikologie, Freie Universität Berlin, Garystrasse 5, 14195 Berlin, Germany. Phone: 49 30 8445-1770. Fax: 49 30 8445-1763. E-mail: stahl{at}medizin.fu-berlin.de.

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Antimicrobial Agents and Chemotherapy, June 2002, p. 1755-1759, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1755-1759.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Pfister, K., Mazur, D., Vormann, J., Stahlmann, R. (2007). Diminished Ciprofloxacin-Induced Chondrotoxicity by Supplementation with Magnesium and Vitamin E in Immature Rats. Antimicrob. Agents Chemother. 51: 1022-1027 [Abstract] [Full Text]