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 across a broad range of doses in relation to its enantiospecific kinetics and adrenergic receptor occupancies, relative to placebo and propranolol. Methods: Twelve healthy male subjects were investigated on six separate occasions at least 1 week apart when they received either a single peroral dose of 40 mg propranolol, 12.5, 25, 50, or 100 mg carvedilol, or placebo. The subjects were extensively profiled at supine rest, 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 determination of alpha1- and beta1-adrenergic receptor binding and related concentrations. Results: Carvedilol was confirmed to bind to beta1-adrenergic receptors and (albeit to a lesser extent) to alpha1-adrenergic receptors. Carvedilol furthermore attenuated the ergometric increase in heart rate in a closely dose-related fashion, which exemplified its beta1-adrenergic receptor blocking effects. However, the basal efferent adrenergic drive might have been too low to show consistent alpha1-blocking properties. The radioreceptor and enantiomer kinetics were proportional with dose. There was no indication that the overall kinetic behavior of contributing active metabolites would differ from that of the S(-)-enantiomer. On average, there was a smooth linear relationship between the ergometric treatment responses and log-transformed dose, log-transformed concentrations of the S(-)-enantiomer, and the radioreceptor assay derived beta1-adrenergic receptor occupancies. Conclusion: The relative complexity of the kinetics of carvedilol (enantiospecific kinetics and dynamics, protein binding, and involvement of active metabolites) does not preclude relatively simple and straight-forward dose-effect and kinetic-dynamic relationships.