1997 Volume 12 Issue 6 Pages 576-588
The metabolism and binding to serum protein of ONO-5046·Na in various animal species were investigated.
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.
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.
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.
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.
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.
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.
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.
