ISSN:
1432-1041
Keywords:
beta-adrenoceptors
;
penbutolol
;
4-hydroxy-penbutolol
;
plasma concentration kinetics
;
plasma protein binding
;
effect kinetics
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
,
Medicine
Notes:
Summary β-adrenoceptor binding of (—) penbutolol and its active metabolite 4-hydroxy-penbutolol to rat reticulocyte membranes was shown in the presence of native human plasma. Due to the high plasma protein binding (∼90%) the apparent Ki-values of penbutolol were shifted 100-fold to the right after inclusion of plasma in the assay; the Ki was ∼40–70 ng/ml. That value is comparable to the IC50-values calculated from clinical studies. The interaction of 4-hydroxy-penbutolol with β-adrenoceptors was not affected to the same extent by inclusion of plasma protein binding ∼80%, apparent Ki-value ∼7 ng/ml. Thus, the active metabolite of penbutolol displays higher potency at β-adrenoceptors in vitro due to its lesser degree of plasma protein binding. A prediction procedure for antagonist activity after penbutolol administration using β-adrenoceptor interaction and plasma concentration kinetics suggests that, in addition to a rapid elimination process from human plasma, a slow elimination phase of penbutolol (or an active metabolite) is necessary to explain the long duration of action observed in clinical studies after a single oral dose. Inhibition in vitro of β-adrenoceptor binding by plasma samples obtained after oral administration of 40 mg penbutolol to 3 healthy volunteers indicated a biphasic concentration-time profile of the antagonist in plasma and was in accordance with the time course of the reported reduction in exercise tachycardia. Finally, plasma concentrations of penbutolol equivalents derived from the receptor assay were in the range of penbutolol concentrations detected by physico-chemical methods. It is concluded that the time course of antagonism against β-adrenoceptor-mediated effects after a single oral dose of penbutolol in man can readily be explained by its biphasic elimination kinetics from human plasma together with the properties of the β-adrenoceptor interaction detectable in vitro.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00544083
Permalink
