Evaluation of toxicokinetic variables and arthropathic changes in juvenile rabbits after oral administration of an investigational fluoroquinolone, PD 117596.
OBJECTIVE
To compare toxicokinetic variables and associated tissue drug concentrations with severity of articular lesions in weight-bearing joints of juvenile rabbits after oral administration of a fluoroquinolone.


METHODS
Ten 6- to 7-week-old, 800- to 1,200-g, New Zealand White rabbits.


METHODS
Rabbits were gavaged daily with the fluoroquinolone PD 117596 at 500 mg/kg of body weight for 5 days. Blood samples were collected on day 4 at preestablished times, up to 24 hours after drug administration. On day 5 gross lesion severity and prevalence were evaluated in the major weight-bearing joints, and tissue specimens were collected (60 minutes after drug administration). Serum and tissue drug concentrations were determined by microbiologic plate assay.


RESULTS
Macroscopically, treatment rabbits had a high prevalence of arthropathy with the distal portion of the femur having the highest prevalence and severity of lesions. Grossly, alterations to articular cartilage included 1 to 4 mm in diameter vesicles or erosions. Histologically, vesicles were identified in the midzone or close to the zone of calcified cartilage of treatment rabbits. Chondrocyte cellularity was reduced in affected areas, and perivesicular regions had reduced staining with Safranin O. Correlation analysis of area under the curve values with total scores for lesion severity had a significant positive relationship.


CONCLUSIONS
Our findings support the use of juvenile rabbits as a model for arthropathic changes induced by fluoroquinolone administration.
Johnson
R J
RJ
Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Canada.
Black
W D
WD
Sigler
R E
RE
Baragi
V M
VM
Gough
A W
AW
D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism; D019902:Chondrocytes / Q000187:drug effects; D004341:Drug Evaluation / Q000662:veterinary*; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D024841:Fluoroquinolones; D007596:Joints / Q000187:drug effects* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008297:Male; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D011817:Rabbits / Q000378:metabolism*; D016474:Weight-Bearing
D000890:Anti-Infective Agents; D015507:Drugs, Investigational; D024841:Fluoroquinolones; D015363:Quinolones; C057711:PD-117596