Telithromycin の遺伝毒性, 抗原性, 腎毒性および聴覚器毒性試験

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The studies on genotoxicity, antigenicity, nephrotoxicity and ototoxicity of telithromycin (TEL) were carried out. As genotoxicity studies, reverse mutation tests using Salmonella typhimurium (TA 1535, TA 1537, TA 98 and TA 100) and Eschrichia coli (WP 2 uvrA), mammalian cell gene mutation test using mouse lymphoma cells (L 5178 YTK+/-), mammalian chromosome aberration test using cultured human lymphocytes were conducted under the conditions with and without a metabolic activation system (S 9 mix). In these studies TEL did not show any mutagenic activity and clastogenic potential. In micronucleus test in mice TEL did not also induce any damage to the chromosomes or the mitotic apparatus in bone marrow cells. As antigenicity studies, homologous active systemic anaphylaxis and passive cutaneous anaphylaxis test in guinea pigs, and IgE production test in mice using heterologous passive cutaneous anaphylaxis in rats were carried out. No positive anaphylaxis responses were observed in guinea pigs and no production of IgE antibodies against TEL were detected in mice. In order to evaluate the nephrotoxicity of TEL, the effects on renal function of normal rats and glycerol-furosemide induced renal impaired model rats were investigated by single oral dosing of the test substance and compared with the effects by single intravenous dosing of cephaloridine (CER). Clear producing and potentiating effects of renal toxicity, proximal tubular epithelium degeneration, epithelial cell vacuolation and tubular dilatation, were observed in those animals treated with CER. Although slight changes in several parameters of urine and blood biochemistry were detected in rats treated with TEL, the histopathological findings of kidneys found in rats treated with TEL were very slight similar to those of control group. TEL administered once orally to female normal and water restricted rabbits did not induce any renal impairment. In order to evaluate the potential ototoxicity of TEL, auditory thresholds test using Brainstem Evocated Responses Audiometry (BERA) and microscopic examination of the inner ear were conducted in rats orally dosed for 4 weeks and compared with the rats treated with kanamycin by intramuscular injection for the same duration. No relevant variations of the auditory thresholds were detected on BERA or at microscopic examination of the inner ear in rats treated with the test substance and also no microscopic changes in the kidneys were observed in this group. As expected, kanamycin induced functional disturbances in the inner ear, significant elevation of auditory thresholds and pathological changes in the kidneys, tubular epithelial degeneration/necrosis.
公益社団法人日本化学療法学会の論文
2003-09-30

Telithromycin の遺伝毒性, 抗原性, 腎毒性および聴覚器毒性試験

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