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

Esmolol is an ultra‐short‐acting beta blocker. Its kinetics was studied in eight healthy subjects after continuous intravenous infusion of 400 μg/kg/min over 2 hr. 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. The distribution and elimination t½s of esmolol averaged 2.03 and 9.19 min. The apparent volume of distribution of esmolol averaged 3.43 l/kg and was four times the volume of the central compartment. The total clearance of esmolol averaged 285 ml/min/kg, indicating that nonhepatic routes play a predominant role in its clearance. The t½s of formation and elimination of the metabolite averaged 2.82 min and 3.72 hr. The ratio of the metabolite formation and elimination rate constants of the parent drug (k f /k 10 ) 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/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 μg/kg/min. There was a strong correlation between the magnitude of these effects and the logarithm of the steady‐state blood concentrations of esmolol. Clinical Pharmacology and Therapeutics (1983) 34, 427–434; doi: 10.1038/clpt.1983.193