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CARDIOVASCULAR

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

Leiden Amsterdam Center for Drug Research, Leiden University, Division of Pharmacology, Leiden, The Netherlands (T.J.v.S., M.D., E.C.M.d.L.); and LAP&P Consultants BV, Leiden, The Netherlands (J.F.)

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 β₁-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 x 10^–8 M; left atria WKY rats). Resulting estimates for baseline (E₀), maximal effect (E_max), and efficacy () 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 (), 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 β₁ -receptor was 4.6 x 10^–8 M. The obtained estimate for in vivo affinity of S(–)-atenolol (4.6 x 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.

Address correspondence to: Dr. Elizabeth C. M. de Lange, Leiden/Amsterdam Center for Drug Research, Leiden University, Division of Pharmacology, PO Box 9502, 2300 RA Leiden, The Netherlands. E-mail: l.lange{at}lacdr.leidenuniv.nl