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The usual therapeutic doses for the treatment of both angina pectoris and cardiac arrhythmia vary widely among beta-blocking agents, with a maximum of about a 200-fold difference, despite subjects' same clinical improvement at the varying doses. In order to clarify the mechanism of this difference, we analyzed retrospectively the cardiac pharmacological activities of beta-blocking agents based on the receptor occupancy theory by using both their unbound concentrations in plasma at steady state (Cssf), as well as dissociation constants (KB and KI, which were determined by in vitro binding experiments and by in vitro pharmacological experiments, respectively) for a beta 1 receptor. A significant log-linear relationship between Cssf and the KB values was obtained with a slope of regression line of 0.91 (r = 0.83, p &lt; 0.01). On the other hand, the correlation coefficient of the relationship between Cssf and the KI values was low, with a slope of about 0.5 (r = 0.80, p &lt; 0.01). The beta 1 receptor occupancies calculated from KB values at the steady state condition after the oral administration of usual doses were almost constant (80.5 +/- 16.8%), regardless of the wide variation of usual doses of the drugs. This result indicated that the receptor occupancy may be an appropriate indicator for the pharmacological activity of the drug. Furthermore, there were significant relationships between the primary pharmacokinetic parameters: Cb/Cf, CLtot/F, and Vdssf, and the octanol/water partition coefficient (PC), with correlation coefficients of 0.80, 0.50 and 0.85, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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Prediction of Therapeutic Doses of Beta-Adrenergic Receptor Blocking Agents Based on Quantitative Structure-Pharmacokinetic/Pharmacodynamic Relationship.