These results suggest that SN-38, which results from the hydrolysis of SN-38 glucuronide by beta-glucuronidase in the intestinal microflora, contributes considerably to the distribution of SN-38 in the large intestine tissue, and that inhibition of the beta-glucuronidase activity by antibiotics results in decreased accumulation of SN-38 in the large intestine.

An approach to minimization of toxicity of a new compound is to elucidate the mechanisms of toxicity of analogous compounds and to clarify their structure-toxicity relationships. A problem with this approach, however, is that such elucidation remains difficult. For quinolones, some improvements in this mechanistic approach have been achieved in the central nervous system (CNS), particularly with regard to their interaction with non-steroidal anti-inflammatory drugs (NSAIDs), and in genotoxicity and phototoxicity studies, particularly in comparison with other toxicities, such as to the cardiovascular, gastrointestinal, bone, reproductive, and developmental systems. This review concentrates on a description of the known effects of quinolones on various organ systems in experimental animals and humans. Given the logarithmic increase in the synthesis of new quinolones, it is questionable whether these drugs share similar safety and efficacy. Nevertheless, this mechanistic approach to the investigation and minimization of toxicity has produced satisfactory results to date and deserves to be continued.

We examined the effects of the quinolone antibacterial agents pefloxacin (PFLX) and ofloxacin (OFLX) on the Achilles tendon of Sprague-Dawley rats. A single oral administration of PFLX 300 and 900 mg/kg or OFLX 900 mg/kg induced edema with mononuclear cell infiltration mainly in the inner sheath of the inner Achilles tendon just proximal to the tuber calcanei in rats killed on the next day. Cell infiltration was also seen in the adjacent synovial membrane and joint space. With progression of severity, the lesions extended to the surface tendon tissue, wherein irregularly arranged collagen bundles were detached from each other and nuclei of fibroblasts were pyknotic and fragmented. After 2-wk repeated administration, these lesions were replaced by fibrotic foci with regenerated tendon fibroblasts, and the incidence and severity were reduced in the OFLX but not PFLX groups. Coadministration of cyclosporin A with OFLX 300 mg/kg induced these lesions despite the fact that neither induced lesions alone. The tendon lesions were induced in juvenile rats (4 wk of age) but not in young adults (12 wk). The articular cartilage of juvenile rats showed focal degeneration and/or cavitation in the tarsal joints after a single and 2-wk administration of PFLX or OFLX. Hydrocortisone slightly increased the incidence of OFLX-induced lesions in both the tendon and cartilage after a 2-wk administration. The occurrence of the tendon lesions is different from that of the Achilles tendon disorders reported in older humans, but they are thought to be a useful model for them.

Fluoroquinolone antibacterial agents have been reported to induce tendon lesions in juvenile rats. In the present study, we characterized fluoroquinolone-induced Achilles tendon lesions by comparing the effects of 10 fluoroquinolones and examining the potential of one of these antimicrobial agents, pefloxacin, to induce tendon lesions when coadministered with one of nine anti-inflammatory compounds. Among the 10 fluoroquinolones tested, fleroxacin and pefloxacin were the most toxic, inducing lesions at a dose of 100 mg/kg of body weight or more, while lomefloxacin, levofloxacin, and ofloxacin or sparfloxacin and enoxacin induced lesions at 300 mg/kg or more and 900 mg/kg, respectively. In contrast, norfloxacin, ciprofloxacin, and tosufloxacin had no effect even at the high dose of 900 mg/kg. The severity of the Achilles tendon lesions appeared to correlate with the structure of the substituent at the seventh position. Furthermore, pefloxacin-induced tendon lesions were inhibited by coadministration with dexamethasone and N-nitro-L-arginine methyl ester. Phenidone (1-phenyl-3-pyrazolidinone) and 2-(12-hydroxydodeca-5,10-diynyl)3,5,6-trimethyl-1,4-benzoqui none (AA861) also decreased the incidence of tendon lesions. In contrast, catalase, dimethyl sulfoxide, indomethacin, pyrilamine, and cimetidine did not modify these tendon lesions. These results suggest that nitric oxide and 5-lipoxigenase products partly mediate fluoroquinolone-induced tendon lesions.

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We investigated the toxic effect of levofloxacin (LVFX), a quinolone antibacterial agent, on cartilage by examining aspects of its in vivo toxicokinetics and effect on the function of cultured chondrocytes of the femoral articular cartilage from juvenile New Zealand White rabbits. Repeated administration of LVFX (100 mg/kg) orally for 7 days induced focal necrosis and superficial erosion in the articular cartilage of the femoral condyle, but 30 mg/kg did not. Concentrations of LVFX in the cartilage were highest at the first sampling point (30 min) after a single administration, being 4.93 and 12.2 g/g in the 30-and 100-mg/kg groups, respectively. The arthropathic concentration of LVFX in the cartilage was then shown to be 12.2 g/g or more. For an in vitro study, chondrocytes were separated from the articular cartilage of the rabbit femoral condyle and cultured for 7 days until confluence. 35SO 4 uptake by cultured chondrocyte sheets was most susceptible to LVFX, decreasing at drug concentrations of 5 g/ml or more in 24-and 48-h cultures but not in a 72-h culture. Furthermore, 3 H-thymidine uptake was decreased at concentrations of 10 g/ml or more in a 48-h culture but not in 24-and 72-h cultures. Rhodamine 123 accumulation was susceptible to inhibition in cultured chondrocytes at an LVFX concentration of 10 g/ml or more. These results suggest that LVFX inhibits glycosaminoglycan synthesis initially and DNA synthesis and mitochondrial function secondarily at actual arthropathic concentrations in cultured rabbit chondrocytes but that these changes are reversible and not enough to kill the cells.Adverse effects of quinolone antibacterial drugs, including arthralgia, joint swelling, arthropathy, and arthritis, have been reported at incidences of less than 0.5% in healthy volunteers and juvenile and adult patients (17). Quinolones are well known to induce cavitation in the articular cartilage of juvenile rats, rabbits, guinea pigs, dogs, marmosets, and crab-eating monkeys but not in that of adults; of these species, dogs are thought to be most susceptible to this chondrotoxicity (4,5,11,12,15,16,24,25,27,29,31). However, the relationship between the adverse clinical effects of these drugs and their toxic lesions in laboratory animals has not been clarified.The initial changes in quinolone-induced toxicity in the articular cartilage of juvenile animals are thought to occur in chondrocytes (6,8,19) or in the matrix (4). In our previous ex vivo study, ofloxacin (OFLX) inhibited the uptake of 3 H-thymidine and 35 SO 4 by the articular cartilage of juvenile rats 12 h after oral administration of a single large dose (20). Considering the inhibitory effect of the drug on topoisomerase II of mammalian cells, we then speculated that the initial target of OFLX in its induction of cartilage damage was the DNA synthesis of chondrocytes. Histopathological examinations by Stahlmann et al. (29) and Burkhardt et al. (6,8) after administration of OFLX and difloxacin revealed mitochondrial swelling and distention of the rough endopla...

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