Receptor binding assays in analysing the bioavailability and pharmacodynamic bioequivalence of active drug moieties

Abstract

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 β₁-adrenoceptor binding component, and by determining the extent to which the active drug moiety in plasma occupied rabbit lung β₁-and rat reticulocyte β₂-adrenoceptors.

The formulations differed markedly in their kinetic characteristics: the peak plasma concentration (C_max) 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 AUC_{0–24 h}-values for the formulations were 700 and 310 ng·h·ml⁻¹, respectively. The C_max for the β₁-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 AUC_{0–24 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 β₁-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 β₁- and β₂-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 β₁-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 β₂-adrenoceptor occupancy of the conventional formulation varied from 20–30%, and that of the sustained-release formulation was 2–17%. At other times the difference in receptor occupancy between the formulations was not significant.

The results demonstrate that plasma concentration-kinetics were more discriminating than β-adrenoceptor-binding in analysing bioequivalence. It was possible to determine the bioavailability of the active ingredient of metoprolol and to study pharmacodynamic bioequivalence by using receptor binding assays.