Mechanism-Based Pharmacodynamic Modeling Of S(-)-Atenolol: Estimation Of In Vivo Affinity For The Beta(1)-Adrenoceptor With An Agonist-Antagonist Interaction Model

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 beta(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 x 10(-8) M; left atria WKY rats). Resulting estimates for baseline (E-0), maximal effect (E-max), and efficacy (tau) 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 (tau), 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 beta(1)-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.