Combined pharmacokinetic and pharmacodynamic studies in man of the adrenergic β1‐receptor antagonist metoprolol *

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Abstract
The adrenergic β1‐receptor antagonist metoprolol was given orally and intravenously in varying doses to healthy volunteers. The effect on the heart rate during exercise was linearly related to the logarithm of the dose and the plasma concentration. The most pronounced effect was obtained during the first exercise test after administration (one hour after oral and 20 minutes after intravenous administration). The effect declined linearly with time (zero‐order kinetics) and at virtually the same rate for all doses investigated. The time for 50% reduction of the maximally registered effect was 6.4 hours after 100 mg metoprolol orally and 5.0 hours after 50 mg.The plasma concentration of metoprolol declined mono‐exponentially with time at a rate corresponding to an elimination half‐life of about three hours. The relationship between the areas under the plasma concentration curves after oral and intravenous administration indicated a bioavailability of 40–50% for the two highest oral doses. In accordance with this the ratio between equipotent oral and intravenous doses was about 2.5.