Mechanism-Based Pharmacodynamic Modeling of S(–)-Atenolol: Estimation of in Vivo Affinity for the β1-Adrenoceptor with an Agonist-Antagonist Interaction Model

• Published in: The Journal of pharmacology and experimental therapeutics 2008-03, Vol.324 (3), p.1234
• Main Authors: Tamara J. van Steeg, Jan Freijer, Meindert Danhof, Elizabeth C. M. de Lange
• Format: Article
• Language: English
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.107.131680

The aim of this study was the development of an agonist-antagonist interaction model to estimate the in vivo affinity of S( –)-atenolol for the β 1 -adrenoreceptor. Male Wistar-Kyoto (WKY) rats were used to characterize the interaction between the model drugs isoprenaline (to induce tachycardia) and S( –)-atenolol. Blood samples were taken to determine plasma pharmacokinetics. Reduction of isoprenaline-induced tachycardia was used as a pharmacodynamic endpoint. The pharmacokinetic-pharmacodynamic relationship of isoprenaline was first characterized with the operational model of agonism using the literature value for the affinity ( K A ) of isoprenaline (3.2 × 10 –8 M; left atria WKY rats). Resulting estimates for baseline ( E 0 ), maximal effect ( E max ), and efficacy (τ) were 374 (1.9%), 130 (5.9%), and 247 (33%) beats per minute, respectively. In addition, the interaction between isoprenaline and S( –)-atenolol was characterized using a pharmacodynamic interaction model based on the operational model of agonism that describes the heart rate response based on the affinity of the agonist ( K A ), the affinity of the antagonist ( K B ), the efficacy (τ), the maximal effect ( E max ), the Hill coefficient ( n H ), the concentrations of isoprenaline and atenolol, and the displacement of the endogenous agonist adrenaline. The estimated in vivo affinity ( K B ) of S( –)-atenolol for the β 1 -receptor was 4.6 × 10 –8 M. The obtained estimate for in vivo affinity of S( –)-atenolol (4.6 × 10 –8 M) is comparable to literature values for the in vitro affinity in functional assays. In conclusion, a meaningful estimate of in vivo affinity for S( –)-atenolol could be obtained using a mechanism-based pharmacodynamic modeling approach.