Contribution of 4‐hydroxy‐alprenolol to adrenergic beta receptor blockade of alprenolol

Alprenolol, like propranolol, is metabolized to a 4‐hydroxy derivative. This study was performed in 6 human volunteers to determine the potency of the metabolite in relation to that of alprenolol with respect to reduction of exercise‐induced tachycardia. The metabolite reached higher plasma levels than alprenolol during the first hours after both single and repetitive oral doses of alprenolol but was not detected in plasma after an intravenous dose. The plasma elimination half‐life for 4‐hydroxy‐alprenolol was one‐third that for alprenolol (0.8 hr and 2.5 hr, p < 0.01). Percentage reduction of exercise heart rate and total plasma levels of alprenolol after a 10‐mg intravenous dose correlated (r = 0.56, p < 0.01). This was generally higher within individuals, since the responsiveness to unchanged alprenolol differs among subjects. The effect‐concentration relationship was slightly higher (r = 0.67) when non‐protein‐bound alprenolol was substituted for total alprenolol. 4‐Hydroxy‐alprenolol contributed to the effect after oral administration of alprenolol; total plasma levels were equipotent with alprenolol. It is concluded that the contribution of the metabolite to effect varied among individuals and was dependent on mode of administration (intravenous or oral), dose, and time after dosage. We also introduce an approach to the evaluation of the activity of drug metabolites in the presence of the parent compound.