Receptor binding assays in analysing the bioavailability and pharmacodynamic bioequivalence of active drug moieties. A study of metoprolol.

The bioavailability and pharmacodynamic bioequivalence of a conventional and an experimental sustained-release formulation of 100 mg metoprolol tartrate were studied in a randomised cross-over study in seven healthy volunteers by assessing over 24 h the plasma kinetics of R,S-metoprolol, its beta 1-adrenoceptor binding component, and by determining the extent to which the active drug moiety in plasma occupied rabbit lung beta 1- and rat reticulocyte beta 2-adrenoceptors. The formulations differed markedly in their kinetic characteristics: the peak plasma concentration (Cmax) of R,S-metoprolol after administration of the conventional formulation was 140 ng.ml-1, (n = 7) and it was approximately one-third of that after the sustained-release formulation, 49 ng.ml-1, (n = 6); the AUC0-24 h-values for the formulations were 700 and 310 ng.h.ml-1, respectively. The Cmax for the beta 1-adrenoceptor binding component of metoprolol was 180 ng.ml-1 (n = 7) after administration of the conventional, and 74 ng.ml-1 after administration of the sustained-release formulation. The corresponding AUC0-24 h-values for the receptor binding component were 920 and 470 ng.h.ml-1 (n = 7). Thus, the kinetic differences between R,S-metoprolol and the beta 1-receptor binding component were considerable and they were affected by the type of formulation. In general, after administration of the sustained-release formulation, the percentage beta 1- and beta 2-adrenoceptor occupancy of metoprolol in plasma was 5-15% less than after administration of the conventional formulation.(ABSTRACT TRUNCATED AT 250 WORDS)