Esmolol, an ultra-short-acting beta-adrenergic blocker, is a racemate. In this study, to compare the stereoselective pharmacokinetics of enantiomers, we have investigated the blood level profile after a single intravenous administration (10 mg/kg) of
14C-esmolol hydrochloride (
14C-esmolol) to dogs. The distribution into the heart, a target organ, was tested after a single intravenous administration (20 mg/kg) of
14C-esmolol to rats. Each enantiomer was tested for metabolic conversion by blood esterase (
in vitro), and the protein binding. In addition, the chiral inversion was investigated using human (
in vitro) and dog blood (
in vitro and
in vivo).
1. The blood concentration and the AUC of
d-esmolol were 1.6-fold higher than those of
l-esmolol, and the half-life of
d-esmolol was 1.7-fold longer than that of
l-esmolol after administration of
14C-esmolol to dogs.
2. The half-life of
d-esmolol was 1.4-fold longer than that of
l-esmolol after incubation with dog blood, whereas no stereoselective difference was found in human blood.
3. The concentration in the heart showed no significant difference between two enantiomers after administration of
14C-esmolol to rats.
4. The chiral inversion was found neither in blood after administration of
14C-
d-esmolol or
14C-
l-esmolol to dogs nor in human and dog blood after the
in vitro incubation.
5. There was no significant difference in protein bindings of each enantiomer after the
in vitro incubation with human, dog and rat serum, and the bound fraction was the highest in human, followed by dog and rat serum.
In conclusion, these findings suggest that pharmacokinetics of enantiomers slightly differ in dog, whereas there are no stereoselective differences in human blood kinetics.
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