Studies on the Metabolic Fate on Ultra Short Acting .BETA.1 Blocker ONO-1101. (2). Plasma Concentration-Time Profile, Distribution, Excretion and Effects on Drug Metabolizing Enzyme Activities after Repeated Intravenous Administration to Rats.
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Plasma concentration-time profile, distribution and excretion of ONO-1101 after repeated intravenous administration were investigated in rats. Also the influence on the hepatic drug metabolizing enzyme activities was examined.<BR> 1. The radioactivity in plasma at 24 hr after each intravenous administration of <SUP>14</SUP>C-ONO-1101 at the dose of 1 mg/kg/day for 7 days was not detected or was around the detection limit. Repeated administration had no effect on plasma concentration-time profile.<BR> 2. Following repeated intravenous admini stration of <SUP>14</SUP>C-ONO-1101 to male rats at the dose of 1 mg/kg, the kidney, liver, lung, trachea contained high levels of radioactivity that declined to about or below detection limit in almost all tissues at 24 hr. Also in skin and carcass, a high degree of radioactivity were observed within 15 min then declined. Compared with a single administration, the elimination of radioactivity in kidney and liver was slightly delayed. But repeated intravenous administration was not associated with any accumulation of radioactivity in organ or tissue.<BR> 3. The daily excretion of radioactivity in urine and feces was constant since 4-th administration. After repeated intravenous administration, the excretion of radioactivity into urine and feces was respectively 89.7, 14.9%, for male, 86.5, 17.0% for female rats.<BR> 4. Repeated intravenous administration of ONO-1101 at the doses of 1, 10, 50 mg/kg/day for 7 days had no effect on microsomal protein content, liver weight and hepatic drug metabolizing enzyme activities.
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