Studies on the Metabolic Fate of Ultra Short Acting β1 Blocker ONO-1101 (3): Metabolism and Protein Binding
1997 Volume 12 Issue 1 Pages 31-41
Details
1997 Volume 12 Issue 1 Pages 31-41
The metabolism of ONO-1101 after intravenous administration was examined in rats and dogs. Beside species-related differences in metabolic rate, the effects of drugs with ester group on the metabolism of ONO-1101 in human plasma and the binding to serum protein were also investigated.
1. After a single intravenous administration of 14C-ONO-1101 in male rats, 81.8% of blood radioactivity at 5 min consisted of M-1, and 2.1% was ONO-1101. Main metabolite in urine and bile was M-1, and ONO-1101 was less than 7.0%.
2. After a single intravenous administration of ONO-1101 in male dogs, the concentrations of ONO-1101 and M-1 in plasma at 5 min were 1.87 μg/ml and 1.35 μg/ml, respectively. At 30 min, M-2, the β-oxidized of M-1, was detected besides ONO-1101 and M-1. Within 24 hr after intravenous administration of ONO-1101, 38.1%, 40.5% and 2.7% of administered dose were excreted to urine as M-1, M-2 and ONO-1101, respectively. Within 8 hr after intravenous infusion, 0.10% and 2.83% of administered dose were excreted to bile as M-1 and ONO-1101, respectively.
3. Enzymatic activity for the hydrolysis of ONO-1101 was higher in rat, human and dog plasma in that order. The major enzyme that hydolyzed ONO-1101 was supposed to be pseudocholinesterase in human plasma and carboxylesterase in rat plasma and dog liver.
4. Acetylcholine and enalapril did not affect t he hydolysis of ONO-1101 inhuman plasma. Procaine and succinylcholine, known as the substrate of pseudocholinesterase, competitively inhibit the hydrolysis of ONO-1101.
5. The serum protein bindings of 14C-ONO-1101 (0.1 μg/ml) in rat, dog and human were 2.8, 21.3 and 1.6%, respectively.
