Stereoselective pharmacokinetics of esmolol enantiomers

摘要

Esmolol,an ultra-short-acting beta-adrenergic blocker,is a racemate.In this study,to compare the stereoselective pharmacokintics of enantiomers,we have investigated the blook level profile after a single intravenous administration (10mg/kg) of ~(I14)C-esmolol hydrochloride (~(14)C-esmolol0 to dogs.The distribution into the heart,a target organ,was tested after a single intravenous administration (20 mg/kg) of ~(14)C-protein binding.In addition,the chiral inversion was investigated using human(in vitro) and dog blood (in vitroand 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-lie of d-esmolol was 1.7-fold longer than that of l-esmolol after administration of ~(14)C-esmolokl 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 ~(14)C-esmolol to rats. 4.The chiral inversion was found neither in blood afte radministration of ~(14)C-d-esmolol or ~(14)C-l-esmolol todogs nor in human and dog blood after the in vitro incubation. 5.There was no significnat 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 differin dog,whereas there are no stereosleective differences in human blood kinetics.