Telithromycin のラットを用いた反復経口投与毒性およびトキシコキネティックス試験

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In order to assess the toxicity of the test article telithromycin (TEL), we conducted a 30-day oral toxicity study with a 4-week recovery period and a 13-week oral toxicity study in male and female Sprague Dawley rats. Toxicokinetic parameters were also evaluated in these studies. In the 30-day study (0, 50, 150 and 300mg/kg/day), a slight decrease in body weight in males, increased liver enzymes in both sexes and liver weights increase in females were noted at 300mg/kg/day. At necropsy, increased size of the cecum, due to the antibacterial effect of the test article on the gut microbial flora, was observed in animals from all dosed groups. In histopathological examination, compound-associated phospholipidosis, a known class effect of macrolide molecules, were observed in the liver, lungs, bile duct, jejunum/ileum and mesenteric lymph nodes at 150 and 300 mg/kg/day and in the spleen at 300 mg/kg/day. As other liver findings, multifocal hepatic necrosis and hepatocellular hypertrophy and/or anisokaryosis were also noted. Compound-related changes were completely or partially resolved after a 4-week treatment-free period. Therefore, 50 mg/kg/day dose is considered to be the no observed adverse effect level. The variability of plasma concentrations within each subgroup was generally moderate. Cmax and AUC at day 30 were increased at 150 and 300 mg/kg/day in female and at 300 mg/kg/day in male, and the accumulation ratios were 2 to 3 at the highest dose in both sexes. In the 13-week oral toxicity study at doses of 0, 20, 50 and 150 mg/kg/day, a slight decrease in body weight in males, increased liver enzymes in both sexes and increased liver weights in females were noted at 150 mg/kg/day. Phospholipidosis-related changes were observed in the liver, lungs and small intestines at 150 mg/kg/day and in the mesenteric lymph nodes and spleen at 50 and 150 mg/kg/day. In addition, focal hepatic necrosis, multinucleated hepatocytes, increased incidence and severity of mononuclear cell infiltrates and single cell necrosis at 150 mg/kg/day. Therefore in 13-week toxicity study also, 50 mg/kg dose is estimated to be the no observed adverse effect level. The variability of plasma concentrations within each subgroup was moderate and C24h increased in a non-linear way. An increase in C24h between day 30 and day 91 was observed at 50 and 150 mg/kg/day in female and at 150 mg/kg in male. At 150 mg/kg/day, mean C24h in female was about 3 times higher than in the males.
公益社団法人日本化学療法学会の論文
2003-09-30

Telithromycin のラットを用いた反復経口投与毒性およびトキシコキネティックス試験

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