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

概要

論文の詳細を見る
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 (C_<ssf>), as well as dissociation constants (K_B and K_I, 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 C_<ssf> and the K_B values was obtained with a slope of regression line of 0.91 (r=0.83,p<0.01). On the other hand, the correlation coefficient of the relationship between C_<ssf> and the K_I values was low, with a slope of about 0.5 (r=0.80,p<0.01). The beta 1 receptor occupancies calculated from K_B 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. Furtheremore, there were significant relationships between the primary pharmacokinetic parameters : C_b/C_f, CL_<tot>/F, and Vd_<ssf>, and the octanol/water partition coefficient (PC), with correlation coefficients of 0.80,0.50 and 0.85,respectively. Accordingly, it is suggested that the prediction of a ususal dose of a new beta-blocking agent can be carried out by using the K_B and PC values based on quantitative structure-Pharmacokinetic/pharmacodynamic relationships. This methodology should be very useful for estimating the rational usual dose of a new beta-blocking agent from the animal experimental and physicochemical data in the preclinical study.
公益社団法人日本薬学会の論文
1993-12-15

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

スポンサーリンク

概要

著者

関連論文

スポンサーリンク