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

Abstract

ABSTRACT. A non-arthropathic dose and disposition of ofloxacin, a potent new quinolone antimicrobial agent, were assessed in male juvenile (3-month-old) dogs, when administered orally at 5, 10 and 20 mg/kg/day once daily for 8 consecutive days. Ofloxacin concentrations in sera and articular cartilages were analyzed by high-performance liquid chromatography (HPLC). Macroscopically, arthropathy characterized by fluid-filled vesicles in articular surface of the humerus and femur was observed in animals receiving 10 and 20 mg/kg/day of ofloxacin, but not in those given 5 mg/kg/day. At 20 mg/kg/day, arthropathy of comparable severity also occurred on day 2. Microscopically, the cavity formation in the middle zone of the articular cartilage was first identified and then necrotic chondrocytes were found numerous around the cavity, followed by appearance of chondrocyte clusters. In pharmacokinetics, peak serum concentration (C max ) and area under the concentrations (AUC 0-24 ) were increased in a dose-dependent manner. However, no remarkable differences in these two parameters were noted between a single and repeated treatments, suggesting no accumulation of the drug. The articular ofloxacin concentration 2 hr after treatment was approximately 1.8 (day 2) to 2.0 times (day 8) higher than the serum concentration. Based on these results, a non-arthropathic dose of ofloxacin in male juvenile dogs following an 8-day treatment is considered to be 5 mg/kg/ day, and its C max , AUC 0-24 and articular cartilage concentrations 2 hr after treatment were 3.4 µg/ml, 35.1 µg⋅hr/ml and 7.0 µg/g, respectively, under these experimental conditions. Thus, arthropathy due to ofloxacin may be predicted by monitoring serum drug concentration. KEY WORDS: arthropathy, juvenile dog, non-arthropathic dose, ofloxacin, pharmacokinetics.J. Vet. Med. Sci. 63(8): 867-872, 2001 New quinolone antimicrobial agents (quinolones) are widely used in clinical fields because of their broad spectra and bactericidal activity. 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. Moreover, they have demonstrated that the initial target of the drug for the induction of arthropathy is the DNA synthesis of chondrocytes. Supporting this hypothesis, several DNA synthesis inhibito...

In Vitro Discrimination of Fluoroquinolones Toxicity on Tendon Cells: Involvement of Oxidative Stress

“…The range of concentrations tested (0.01 M-1.0 mM) in- cluded the peak plasma concentrations seen in humans with the four fluoroquinolones tested (5.6 -30 M after a single oral dose of 500 mg) and the highest concentrations observed in articular tissue (Meissner et al, 1990;Yabe et al, 2001). Recently, Yabe et al (2001) reported that intraarticular OFX concentrations in juvenile dogs were approximately 1.8 to 2.0 times higher than the serum concentration 2 h after dosing.…”

“…Recently, Yabe et al (2001) reported that intraarticular OFX concentrations in juvenile dogs were approximately 1.8 to 2.0 times higher than the serum concentration 2 h after dosing. Similarly, Meissner et al (1990) reported that halflife of OFX was longer in synovial tissues than in serum.…”

Inhibitory effect of several fluoroquinolones on hepatic microsomal cytochrome P‐450 1A activities in dogs

“…These doses may result in C max <10 μ g/mL ( c . 0.03 m m ) at most, based on their pharmacokinetics after oral administration as a single dose in dogs (Yabe et al. , 2001 for OXF Boothe et al.…”

“…That of NFX is 11-22 mg/kg/day. These doses may result in C max <10 lg/mL (c. 0.03 mM) at most, based on their pharmacokinetics after oral administration as a single dose in dogs (Yabe et al, 2001for OXF Boothe et al, 2002for EFX, Kay-Mugford et al, 2002for OBFX, Wallis et al, 1996. Although CFX is not used for animal therapy, it is detected in plasma as a metabolite of EFX, and its C max has been reported to be nearly 2 lg/mL (0.009 mM) after the highest dose of EFX (Boothe et al, 2002).…”

Chondrotoxicity of Quinolone Antimicrobial Agents

“…In juvenile animals, quinolone concentrations are generally higher in the articular cartilage than in plasma. The lowest arthropathogenic concentrations have been reported to be 20.6, 9.4 and 6.9 µg/g for norfloxacin and 34.1, 21.5 and 4.6 µg/g for nalidixic acid in juvenile rats, rabbits and dogs, respectively 7 ; 12.2 µg/g for levofloxacin in juvenile rabbits 51 ; and 8.7 µg/g for ofloxacin in juvenile dogs 67 . On the other hand, there is only very limited data for humans: the mean ofloxacin cartilage concentrations are 1.38, 2.19 and 2.18 kg/l (assuming an average bone density of 1.9 kg/l) at 98, 246 and 716 min after completion of 20 min infusion of 200 mg ofloxacin to 23 adult patients who underwent total hip replacement for osteoarthritis 68 .…”