Chondrotoxicity and toxicokinetics of sparfloxacin in juvenile rats.
Sparfloxacin is a fluoroquinolone with improved antibacterial activity against gram-positive pathogens. Like other quinolones, use of this drug is contraindicated in children and adolescents because of its potential chondrotoxicity in juveniles. We performed histological and immunohistochemical studies on the knee joint cartilage in 5-week-old rats after treatment with 600 or 1,800 mg of sparfloxacin/kg of body weight. Treatment with single or multiple oral doses of 600 mg of sparfloxacin/kg was not sufficient to induce joint cartilage lesions. However, five of eight rats treated with a single oral dose of 1,800 mg of sparfloxacin/kg of body weight showed typical cartilage lesions in the femoral part of the knee joint. The concentrations of the drug in plasma measured 0.25, 0.75, 1.5, 3, 6, 12, and 24 h after the administration of an oral dose of 600 mg of sparfloxacin/kg were 6.3 +/- 1.8, 9.2 +/- 1.7, 9.6 +/- 2.7, 13.0 +/- 1.8, 12.3 +/- 1.6, 3.4 +/- 0.4, and 0.30 +/- 0.20 mg/liter, respectively (mean +/- standard deviation [SD]; n = 5 to 6 per group). The concentrations in plasma measured 0.75, 1.5, 3, 6, 24, and 48 h after the administration of an oral dose of 1,800 mg of sparfloxacin/kg were 10.9 +/- 1.5, 15.9 +/- 1.6, 19.1 +/- 1.7, 14.9 +/- 3.1, 4.1 +/- 0.6, and 0.46 +/- 0.37 mg/liter, respectively (mean +/- SD; n = 3 to 4 per group). The concentrations of sparfloxacin in joint cartilage were significantly higher at all time points studied (114.8 +/- 80, 99.4 +/- 31.5, 84.9 +/- 16.8, 44.4 +/- 13.9, and 14.2 +/- 4.8 mg of sparfloxacin/kg at 1.5, 3, 6, 24, and 48 h after the administration of 1,800 mg/kg, respectively). The range of concentrations in bone were similar to the range of concentrations in cartilage (peak, 115 +/- 12 mg/kg after 3 h). Our data indicate that chondrotoxic doses of sparfloxacin in juvenile rats are approximately 300 times higher than the doses of sparfloxacin used therapeutically (1,800 versus approximately 6 mg/kg of body weight), but due to species differences in kinetics, concentrations in plasma differ by a factor of only approximately 15. More data on quinolone concentrations in cartilage from animals and humans could provide a better basis for a reasonable risk assessment.
Stahlmann
R
R
Institut für Klinische Pharmakologie und Toxikologie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Germany. stahl@medizin.fu-berlin.de
Zippel
U
U
Förster
C
C
Schwabe
R
R
Shakibaei
M
M
Merker
H J
HJ
Borner
K
K
D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D024841:Fluoroquinolones; D007150:Immunohistochemistry; D007719:Knee Joint / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015363:Quinolones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D015363:Quinolones; C061363:sparfloxacin