DOSE-EFFECT AND PHARMACOKINETIC-PHARMACODYNAMIC RELATIONSHIPS OF THE BETA(1)-ADRENERGIC RECEPTOR BLOCKING PROPERTIES OF VARIOUS DOSES OF CARVEDILOL IN HEALTHY HUMANS

Objective: To evaluate the pharmacodynamic properties of carvedilol ac ross a broad range of doses in relation to its enantiospecific kinetic s and adrenergic receptor occupancies, relative to placebo and propran olol. Methods: Twelve healthy male subjects were investigated on six s eparate occasions at least 1 week apart when they received either a si ngle peroral dose of 40 mg propranolol, 12.5, 25, 50, or 100 mg carved ilol, or placebo. The subjects were extensively profiled at supine res t, and they underwent supine bicycle ergometry before and at 2, 4, 6, 9, 12, and 22 hours after dosing. At these time points blood was drawn for the high performance liquid chromatographic determination of the enantiomers of carvedilol and for the radioreceptor assay determinatio n of alpha1- and beta1-adrenergic receptor binding and related concent rations. Results: Carvedilol was confirmed to bind to beta1-adrenergic receptors and (albeit to a lesser extent) to alpha1-adrenergic recept ors. Carvedilol furthermore attenuated the ergometric increase in hear t rate in a closely dose-related fashion, which exemplified its beta1- adrenergic receptor blocking effects. However, the basal efferent adre nergic drive might have been too low to show consistent alpha1-blockin g properties. The radioreceptor and enantiomer kinetics were proportio nal with dose. There was no indication that the overall kinetic behavi or of contributing active metabolites would differ from that of the S( -)-enantiomer. On average, there was a smooth linear relationship betw een the ergometric treatment responses and log-transformed dose, log-t ransformed concentrations of the S(-)-enantiomer, and the radiorecepto r assay derived beta1-adrenergic receptor occupancies. Conclusion: The relative complexity of the kinetics of carvedilol (enantiospecific ki netics and dynamics, protein binding, and involvement of active metabo lites) does not preclude relatively simple and straight-forward dose-e ffect and kinetic-dynamic relationships.