Pharmacokinetics and Pharmacodynamics of Flestolol, a New Short‐Acting, Beta‐Adrenergic Receptor Antagonist

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Abstract
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 μg/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 μg‐hr/mL, respectively. Flestolol did not cause any significant change (P > .05) in the heart rate or systolic or diastolic blood pressure from the baseline. Flestolol significantly (P < .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.CONCLUSIONThe results of this study show that there is little intersubject variability in the disposition of flestolol. The drug is rapidly eliminated from blood, and it is cleared mainly by extrahepatic routes. Flestolol is an effective beta‐adrenergic blocking agent and exhibits both a rapid onset and short duration of action. None of the subjects experienced clinically significant adverse effects, and there were no clinically significant alterations in the blood chemistry, hematology, or creatinine clearance in any participant during the flestolol‐infusion period. Although infusion site induration was observed in three subjects, it did not necessitate discontinuation of infusion. Furthermore, in another investigation, subjects tolerated flestolol at the same dosage level for seven days.