好中球エラスターゼ阻害剤ＯＮＯ‐５０４６・Ｎａの体内動態（第３報）　各種実験動物における代謝および血清蛋白結合

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  • Studies on the Metabolic Fate of Neutrophil Elastase Inhibitor ONO-5046Na(3): Metabolism and Binding to Serum Protein in Various Animal Species.

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The metabolism and binding to serum protein of ONO-5046·Na in various animal species were investigated.<BR> 1. The structure of main metabolite (M-1) in the rat was confirmed by comparison with authentic sample (ONO-EI-601) using LC/MS/MS. Also the sulfate and glucuronide of M-1 were found.<BR> 2. The plasma composition of ONO-5046·Na and its metabolites was investigated after intravenous administration of 14C-ONO-5046·Na (dose: 1 mg/kg) to male and female rats. At 15 min after administration, 25.5 ?? 26.5% of plasma radioactivity consisted of ONO-5046·Na and 56.6 ?? 67.5% consisted of M-1. The plasma concentration of M-1 sulfate in male rats was about 10 times higher than that in female rats. At 2 hr after administration to male and female rats, the main metabolite in plasma was M-1.<BR> 3. The urine composition of metabolites was investigated after intravenous administration of 14C-ONO-5046·Na (dose: 1 mg/kg) to male and female rats. ONO-5046·Na was hardly detected in urine, and most of the radioactivity was presented by M-1. The excretion rate of M-1 sulfate in male rats was about 3.5 times higher than that in female rats.<BR> 4. The bile composition of metabolites was investigated after intravenous administration of 14C-ONO-5046·Na (dose: 1 mg/kg) to male and female rats. The rate of excretion of ONO-5046·Na in bile was below 0.1% of the dose. No sex-related difference was observed in the excretion rate of M-1 glucuronide and M-1, and the rate of M-1 sulfate in male rats was about 3.5 times higher than that in female rats.<BR> 5. ONO-5046·Na was stable in rat, dog and human plasma and hydrolyzed in a short time by liver 9000×g supernatant of rat and dog.<BR> 6. The serum protein binding of 14C-ONO-5046·Na (10 μg/ml) in rat, dog, hamster and human were 99.6, 96.7, 99.6 and 99.6%, respectively. In all species, serum protein binding decreased when the concentration of ONO-5046·Na was more than 60 μg/ml.<BR> 7. At 5 and 30 min after intravenou s bolus administration of 14C-ONO-5046·Na (dose: 1 mg/kg) to male rats, serum protein binding were 99.79 and 99.07%, respectively.

収録刊行物

  • 薬物動態

    薬物動態 12 (6), 576-588, 1997

    日本薬物動態学会

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