Observations on the clinical pharmacology and plasma concentrations of diacetolol, the major human metabolite of acebutolol.

Abstract

1 The pharmacological effects and plasma levels of diacetolol, the major human metabolite of acebutolol, were measured in a double-blind, balanced study in which five healthy men received single oral doses of diacetolol 100, 200, 400 and 800 mg, or placebo, at weekly intervals.2 Resting and exercise heart rate (HR), forced expiratory volume in 1 second (FEVy), resting and exercise peak expiratory flow rate (PEFR), and plasma concentrations of diacetolol were determined at 0, 2, 4, 6, 8 and 24 h after each treatment. 3 Diacetolol caused a slight dose-related reduction in resting HR and a substantial dose-related reduction in exercise HR. At the same time it was found that diacetolol had no significant effects on FEV, and resting and exercise PEFR. 4 Mean highest observed plasma concentrations (ng/ml) of diacetolol were 177 at a mean of 4.4 h after the 100 mg dose, 243 at 4.0 h after the 200 mg dose, 807 at 5.2 h after the 400 mg dose, and 1,306 at 4.4 h after the 800 mg dose. 5 Using the mean data, there was a strong correlation (r = 0.90) between % reduction in exercise HR and the logarithm of the plasma concentration of diacetolol. 6 Diacetolol exhibits marked cardiac -adrenoceptor blocking activity in man which is still evident 24 h after the administration of the higher doses of the drug. No adverse effects on pulmonary function could be detected.

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…39), a pharmacologically active metabolite with a longer half-life than the parent (and similarly low plasma protein binding) which permits once-per-day dosing (Coombs et al, 1980;DeBono et al, 1985;Piquette-Miller et al, 1991). Diacetolol has been shown to have activity by direct administration to humans (Ohashi et al, 1981). While data on the in vitro potency at the human receptor are not reported, considerable exploration of the relative effects of acebutolol and diacetolol has been done in animals and using animal tissues.…”

A Pharmacokinetic Study of Acebutolol in Aged Subjects as Compared to Young Subjects

“…After oral administration, a phar macologically active metabolite [7,13] diace tolol, appears in plasma [21]. We thought it of interest to determine the influence of age on the pharmacokinetics of these two sub stances.…”