Pharmacokinetic disposition and arthropathic potential of oral ofloxacin in dogs

Abstract

We examined the relation between the pharmacokinetic disposition and arthropathic potential of ofloxacin, a new quinolone antibacterial agent, using both male immature (3-month-old) and mature (18-month-old) beagles. Ofloxacin was orally administered to these dogs at 20 mg/kg once daily for 8 consecutive days, and the animals were killed 2 h after the last treatment. Serum ofloxacin concentrations were repeatedly measured on days 1 and 7 by use of high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were calculated. In addition, on day 8, the drug concentrations in the joint synovial fluid and humeral and femoral condyles were measured. Clinico-pathological tests of blood and serum or histopathological examination of bone specimens were also performed. Arthropathy was macroscopically observed in the cartilage surface of all immature dogs, but not in mature dogs. There were, however, no noticeable differences in pharmacokinetic parameters between the two age groups of dogs or between single and 7-day treatments. In contrast to the occurrence of arthropathic lesions, the synovial fluid and condylar drug concentrations in immature dogs was equal to or lower than those in mature dogs, suggesting that the pharmacokinetic disposition of ofloxacin may not be essential for cartilage lesions.

A Non-Arthropathic Dose and Its Disposition Following Repeated Oral Administration of Ofloxacin, a New Quinolone Antimicrobial Agent, to Juvenile Dogs.

“…Meanwhile, the pharmacokinetic analysis revealed a linear relationship between absorption following oral administration and tissue distribution. Ofloxacin concentrations in sera and articular cartilages obtained in the 20 mg/ kg/day group were also compatible with those of the previous report [23]. At the non-arthropathic dose (5 mg/kg/ day), the C max , AUC 0-24 and articular cartilage concentrations were 3.4 µg/ml, 35.1 µg⋅hr/ml and 7.0 µg/g, respectively.…”

“…In our previous report [23], the arthropathic lesion due to ofloxacin was observed only in juvenile dogs, despite the fact that the drug concentration in the synovial fluid and articular cartilage of immature dogs (3-month-old) was equal to or lower than those in mature dogs (18-month-old). Kato and coworkers [10] have indicated that metabolically active immature chondrocytes are more sensitive to the effects of a quinolone, compared with inactive mature cells in the ex vivo study using 3 H-thymidine.…”

“…However, quinolones have been reported to induce arthropathy in juvenile animals such as mice [12], rats [4, 9, 10], rabbits [11], dogs [3, 5, 8, 20], nonhuman primates [17] and others [1, 2] as a class effect of these derivatives. Among these species, the juvenile dog is thought to be most susceptible to articular cartilage lesions [6,19,20].In our previous report [23], the arthropathic lesion due to ofloxacin was observed only in juvenile dogs, despite the fact that the drug concentration in the synovial fluid and articular cartilage of immature dogs (3-month-old) was equal to or lower than those in mature dogs (18-month-old). Kato and coworkers [10] have indicated that metabolically active immature chondrocytes are more sensitive to the effects of a quinolone, compared with inactive mature cells in the ex vivo study using 3 H-thymidine.…”

“…In the 20 mg/kg/day group, three further animals were sacrificed 2 hr following the second administration on day 2 in the same manner. The dosage levels used in the present investigation were selected from previously published reports [22,23]. Sera separated from the blood and articular cartilage samples were frozen at -30°C until assay.…”

“…Ofloxacin assay: The ofloxacin concentration was assayed by the HPLC method described previously [23]. Briefly, the serum sample (50 µl) was diluted with 0.5% KH 2 PO 4 (pH 2.9) to yield an appropriate concentration within the detectable limit.…”