The comparative arthropathy of fluoroquinolones in dogs.
1. Fluoroquinolone antibiotics are generally only prescribed to paediatric patients on compassionate grounds. This is because they are known to cause lesions in the cartilage of the major diarthroidal joints in immature experimental animals. As dogs are considered to be the most sensitive species, a series of studies was performed to compare the potential for grepafloxacin (a new fluoroquinolone) to cause arthropathy to that of ofloxacin and ciprofloxacin in juvenile (3 month old) beagles. 2. Grepafloxacin was administered once daily to male juvenile dogs at dosages of up to 100 mg/kg/day (intravenously), 60 mg/kg/day (orally) or 30 mg/kg/day (subcutaneously) for 1 week. Blister formation was observed on the surface of the joints in one of the three animals treated with grepafloxacin intravenously at 100 mg/kg/day. No abnormalities were observed at lower dosages or when grepafloxacin was administered orally or subcutaneously, regardless of dose. In animals treated with ofloxacin or ciprofloxacin at dosages of 10-30 mg/kg/day, blister formation or erosion was observed on the surface of joints regardless of dose or route of administration. 3. Histopathological examination of the joint surfaces of affected animals revealed the loss of cartilaginous matrix and chondrocytes, cavitation within the intermediate zone of cartilage accompanied by cartilage fibrillation or chondrocyte clustering, or loss of the surface layer which covers the cavitation (or loss of outer wall of the cavity). These findings were not present in the absence of grossly observed lesions. 4. Absorption following oral administration of grepafloxacin was low. Examination of plasma concentrations of drug following intravenous administration showed that joint toxicity was seen with ofloxacin and ciprofloxacin at maximum concentrations as low as 3.80 and 4.24 mg/l, respectively, while plasma levels of grepafloxacin of up to 11.95 mg/l failed to cause such lesions. When the concentration of grepafloxacin was 18.69 mg/l a single joint lesion was seen. Following subcutaneous administration of grepafloxacin, systemic exposure (area under the curve) of approximately 1.5 times that seen in man was not associated with joint lesions. However, lesions were noted for ofloxacin and ciprofloxacin treated animals at exposures equal to or below those seen in man. Therefore grepafloxacin appeared to have a relatively low potential for joint toxicity; this was not due to lack of penetration into the synovial fluid.
Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd, Japan.
T
T
Takizawa
K
K
Hashimoto
T
T
Minami
S
S
Yamashita
K
K
Owen
D000818:Animals; D000890:Anti-Infective Agents / Q000097:blood / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002939:Ciprofloxacin / Q000097:blood / Q000633:toxicity; D004285:Dogs; D004435:Eating / Q000187:drug effects; D024841:Fluoroquinolones; D007592:Joint Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D015242:Ofloxacin / Q000097:blood / Q000633:toxicity; D010879:Piperazines / Q000097:blood / Q000633:toxicity; D013582:Synovial Fluid / Q000378:metabolism
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D010879:Piperazines; D002939:Ciprofloxacin; D015242:Ofloxacin; C075375:grepafloxacin