Kinetics of esmolol, an ultra-short-acting beta blocker, and of its major metabolite

Abstract

Esmolol is an ultra-short-acting [cardioselective] .beta. blocker. Its kinetics was studied in 8 healthy subjects after continuous i.v. infusion of 400 .mu.g/kg per min over 2 h. The concentrations of esmolol and its major metabolite, 3-[4-(2-hydroxy-3-{isopropylamino} propoxy)phenyl]propionic acid, in blood and urine were determined by gas chromatographic-mass spectrometric assay and HPLC [high performance liquid chromatography]. The distribution and elimination t1/2 [half-life] of esmolol averaged 2.03 and 9.19 min. The apparent volume of distribution of esmolol averaged 3.43 l/kg and was 4 times the volume of the central compartment. The total clearance of esmolol averaged 285 ml/min per kg, indicating that nonhepatic routes play a predominant role in its clearance. The t1/2 of formation and elimination of the metabolite averaged 2.82 min and 3.72 h. The ratio of the metabolite formation and elimination rate constants of the parent drug (kf/k10) averaged 0.829, suggesting that 82.9% of esmolol was converted to the metabolite (which is consistent with the urinary recovery of 71% of the dose as unconjugated metabolite). The volume of distribution and total clearance of the metabolite averaged 0.411 l/kg and 1.28 ml/min per kg. Esmolol was followed by a significant reduction of isoproterenol-induced increase in heart rate and systolic blood pressure at doses of 50, 150 and 400 .mu.g/kg per min. There was a strong correlation between the magnitude of these effects and the logarithm of the steady-state blood concentrations of esmolol.