Metabolism and urinary excretion of esmolol in humans.

The urinary excretion patterns of esmolol, a short-acting beta blocker, and its major metabolite were investigated in eight healthy men after intravenous infusion of 50, 100, 200, and 300 micrograms/kg/min of esmolol for six hours and 150 micrograms/kg/min for 24 hours. Esmolol and the metabolite concentrations in urine were determined by high-performance liquid chromatography. The mean urinary recoveries of the unchanged drug were 0.64%, 0.67%, 0.69%, 0.77%, and 0.98% after the 50, 100, 150, 200, and 300 micrograms/kg/min dose, respectively. Recovery of the metabolite was independent of dose, and the overall mean recovery accounted for 73% of administered dose. The results of this study indicate that esmolol is extensively metabolized, and the extent of the metabolism is not dose related in the dosage range used. The renal route plays a very minor role in the elimination of the drug but is important for the elimination of the metabolite.

Pharmacokinetics and pharmacodynamics of flestolol, a new short-acting, beta-adrenergic receptor antagonist.

The pharmacokinetics and pharmacodynamics of flestolol, a new short-acting, beta-adrenergic receptor antagonist, were examined in nine healthy subjects after a constant intravenous infusion of 5 micrograms/kg/min for 72 hours. Flestolol blood levels were determined by high-performance liquid chromatography. In all subjects, flestolol blood concentration attained steady state 30 minutes after initiation of infusion. The mean +/- standard deviation steady-state concentration of flestolol was 31.1 +/- 12.0 ng/mL. The elimination half-life averaged 7.2 minutes. The mean +/- standard deviation total body clearance was 181 +/- 66 mL/min/kg. The apparent volume of distribution and the area under the curve averaged 1.89 L/kg and 2.23 micrograms-hr/mL, respectively. Flestolol did not cause any significant change (P greater than .05) in the heart rate or systolic or diastolic blood pressure from the baseline. Flestolol significantly (P less than .05) attenuated the isoproterenol-induced increase in heart rate and systolic blood pressure and decrease in diastolic blood pressure in comparison with baseline. The average maximum reduction in isoproterenol tachycardia was in the range of 63% to 79% during flestolol infusion. There was a rapid recovery from beta blockade after termination of flestolol infusion; the recovery averaged 96% 20 minutes after the infusion was stopped. We conclude that flestolol exhibits a very short half-life and is cleared mainly by extrahepatic routes. It is an effective beta blocker and possesses a short duration of action.

Pharmacokinetics of esmolol in hepatic disease.

Esmolol is an intravenous beta blocker with a short duration of action. The pharmacokinetics of esmolol and its acid metabolite, ASL-8123, were studied in nine patients who had stable, biopsy-proved Laennec's cirrhosis and in three normal volunteer controls. Kinetics were determined after a four-hour continuous infusion of esmolol at a rate of 200 micrograms/kg/min. Blood samples were collected during the infusions and at frequent intervals thereafter. The parameters studied were the steady state concentration, the total body clearance, the elimination half-life, the area under the curve, and the volume of distribution. No significant differences in any of these parameters were detected between control subjects and those with hepatic disease, for either esmolol or its acid metabolite. It is concluded from this study that Laennec's cirrhosis does not cause any change in the pharmacokinetics of esmolol or its major metabolite. Therefore, adjustments in dosage of esmolol are not required for patients with Laennec's cirrhosis.

Liquid-chromatographic analysis for esmolol and its major metabolite in urine.

We describe a simple, reproducible liquid-chromatographic method for determination of esmolol (a short-acting beta blocker) and its major metabolite in human urine. Esmolol is extracted from urine at a pH of 8.4 into methylene chloride; the more polar metabolite remains in the aqueous phase. We then measure esmolol with a muBondapak C18 column and measure ultraviolet absorbance at 229 nm; the metabolite is analyzed with a Spherisorb phenyl column, with absorbance measured at 280 nm. The average extraction recoveries of esmolol and the metabolite were 95 and 92%, respectively. Standard curves were linear and reproducible for esmolol from 0.025 to 5 mg/L and for the metabolite from 1 to 250 mg/L. Within-day CVs for both compounds were less than 6%.

Pharmacokinetics of flestolol in man: preliminary data.

The steady state pharmacokinetics of flestolol, a short acting beta-adrenoceptor blocking agent, were studied in six healthy subjects following intravenous infusion of six different doses; 18, 24, 35, 50, 75 and 100 micrograms kg-1 min-1, for 60 min. Steady state blood levels increased linearly with dose for all six subjects. The overall mean half-life was 6.5 min. The total body clearance averaged 208 ml min-1 kg-1 indicating significant extrahepatic metabolism of the drug. There were no significant changes in the half-lives or the total body clearances after the six doses, suggesting that the kinetics of flestolol are linear over the dose range studied.

Pharmacokinetics of esmolol in anesthetized patients receiving chronic beta blocker therapy.

The pharmacokinetics of esmolol, a new, ultra-short-acting beta adrenergic blocking drug, were studied in 19 patients undergoing coronary artery surgery. Esmolol was administered as a continuous infusion, and blood concentrations were measured at intervals up to 40 min after discontinuation of the infusion. In all patients, a bi-exponential equation best described the esmolol concentration--time curve. Half-lives for the distribution and elimination phases were 1.34 +/- 0.77 min and 9.9 +/- 4.55 min (mean +/- SD), respectively. The mean values for V beta and V epsilon were 1.9 +/- 1.24 l X kg-1 and 0.41 +/- 0.31 l X kg-1, respectively, and the total clearance was 128 +/- 41 ml X kg-1 X min-1.