Receptor binding assays in analysing the bioavailability and pharmacodynamic bioequivalence of active drug moieties |
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Authors: | T Kaila L Roivas P J Neuvonen |
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Institution: | (1) Department of Clinical Pharmacology, University of Turku, Turku, Finland;(2) Department of Pharmacology, University of Turku, Turku, Finland;(3) Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland;(4) Department of Clinical Pharmacology, University of Turku, Kiinamyllynkatu 10, SF-20520 Turku, Finalnd |
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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 1-adrenoceptor binding component, and by determining the extent to which the active drug moiety in plasma occupied rabbit lung 1-and rat reticulocyte 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 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 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 1- and 2-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 1-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 2-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 -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. |
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Keywords: | Metoprolol bioavailability bioequivalence receptor binding assay pharmacokinetics sustained release formulation |
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