Studies on the Metabolic Fate of Neutrophil Elastase Inhibitor ONO-5046Na (2): Plasma concentration-profile, Distribusion and Excretion after Repeated Intravenous Bolus Administration to Rats and Effects on Metabolizing Enzyme Activities.

Abstract

The plasma concentration-time profile, distribution and excretion after repeated bolus intravenous administrations of 14C-ONO-5046·Na were investigated in rats. In addition, the effects of repeated administration of ONO-5046·Na on the hepatic drug metabolizing enzyme activities were also examined. 1. Pharmacokinetic parameters after repeated intravenous administration of 14C-ONO-5046·Na at the dose of 1 mg/kg/day for 7 days to male and female rats were not different from those after a single administration. 2. After repeated intravenous administrations of 14C-ONO-5046·Na at the dose of 1 mg/kg/day for 7 days to male rats, the radioactivity in almost all organs decreased rapidly with similar to patterns observed after the single administration. 3. During 7 days repeated intravenous administration, the radioactivity was excreted into urine and feces constantly. Cumulative excretion rates in urine until 72 hr after final dosing of repeated administration to male and female rats were 71.9% and 93.9%, and the cumulative excretion rates in feces were 33.4% and 14.3%, respectively. 4. No change was observed in microsomal protein content and hepatic drug metabolizing enzyme activities under repeated intravenous administration of ONO-5046·Na at the dose of 1, 10 and 30 mg/kg/day to male rats for 7 days.