QUANTITATIVE ESTIMATION OF MYOCARDIAL FIBROSIS BASED ON RECEPTOR OCCUPANCY FOR .BETA.2-ADRENERGIC RECEPTOR AGONISTS IN RATS

TANAKA Satoru, MOMOSE Yasunori, TSUTSUI Masaru, KISHIDA Tomoyuki, KURODA Junji, SHIBATA Nobuo, YOSHIDA Takemi, YAMAGISHI Ryoichi

doi:10.2131/jts.29.179

- To develop β₂-adrenergic receptor (AR) agonists with higher selectivity, it is essential to evaluate the cardiac side effects which are the most serious side effects of this class of drugs. We studied receptor occupancy of β₁-ARs in rats as a possible cause for the side effect of β₂-AR agonists, namely myocardial fibrosis. Myocardial fibrosis in rats was observed on Day 7 after the administration of salbutamol and terbutaline, both of which are selective β₂-AR agonists, at higher dose levels. To evaluate receptor occupancy, plasma concentrations of (R)-salbutamol and (R)-terbutaline, plasma protein binding and the EC₅₀ for chronotropic effects in rats were determined. Based on the plasma concentrations, the plasma protein binding and EC₅₀, receptor occupancy-time profiles were constructed. The relationship between the receptor occupancy-time profile under the curve, the AUCΦ, and the degree of myocardial fibrosis was evaluated with a multiple correlation analysis. Myocardial fibrosis was significantly correlated (r² > 0.78) to the AUCΦ with the threshold above approximately 50%, but not to plasma concentrations. These results indicate that the receptor occupancy theory is also useful for the evaluation of the chronotropic side effects of β₂-AR agonists.<br>

QUANTITATIVE ESTIMATION OF MYOCARDIAL FIBROSIS BASED ON RECEPTOR OCCUPANCY FOR .BETA.2-ADRENERGIC RECEPTOR AGONISTS IN RATS

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