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 Β’/1-adrenoceptor binding component, and by determining the extent to which the active drug moiety in plasma occupied rabbit lung illand rat reticulocyte fl2-adrenoccptors.
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 -~, (n = 7) and it was approximately one-third of that after the sustained-release formulation, 49 ng. ml-~, (n = 6)', the AUC0_24 h-values for the formulations were 700 and 310 ng-h.m1-1, respectively. The Cm~x for the j31-adrenoceptor binding component of metoprolol was 180 ng.rn1-1 (n --7) after administration of the conventional, and 74 ng. ml-z after administration of the sustained-release formulation. The corresponding AUC0_24h-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 fl~-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 A-and fl2-adrenoceptor occupancy of metoprolol in plasma was 5-15 % less than after administration of the conventional formulation. At 0.5-1.5 h after drug intake the average fl~-adrenoceptor occupancy of the conventional formulation varied between 80-90 % and that of the sustained release formulation between 20-76 %. At these times the differences in receptor occupancy were significant; at 0.5-2 h after drug intake the average fl2-adrenoceptor occupancy of the conventional formulation varied from 20-30 %, and that of the sustained-release formulation was 2-17 %. At other times