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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on December 27, 2007; DOI: 10.1124/jpet.107.131680

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Tamara J. van Steeg
Jan Freijer
Meindert Danhof
Elizabeth C.M. de Lange
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*ATENOLOL


Received for publication September 17, 2007.
Revised December 20, 2007.
Accepted for publication December 20, 2007.

Mechanism-based pharmacodynamic modeling of S(-)-Atenolol: Estimation of in vivo affinity for the beta1-adrenoceptor with an agonist-antagonist interaction model

Tamara J. van Steeg 1, Jan Freijer 2, Meindert Danhof 3, Elizabeth C.M. de Lange 3*

1 LAP&P Consultancy 2 Astellas Pharma Europe BV 3 LACDR / Pharmacology

* Address correspondence to: E-mail: l.lange{at}lacdr.leidenuniv.nl

Abstract

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 beta1-adrenoreceptor. Male Wistar Kyoto 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 model using the literature value for the affinity (KA) of isoprenaline (3.2x10-8 M; left atria WKY rats). Resulting estimates for baseline (E0), maximum effect (Emax) and efficacy ({tau}) were 374 (1.9%) bpm, 130 (5.9%) bpm and 247 (33%) respectively. Secondly, 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 on the basis of affinity of the agonist (KA), the affinity of the antagonist (KB), the efficacy ({tau}), the maximum effect (Emax), the Hill coefficient (n), the concentrations of isoprenaline and atenolol, as well as the displacement of the endogenous agonist adrenalin. The estimated in vivo affinity (KB) of S(-)-atenolol for the beta1-receptor was 4.6x10-8 M. The obtained estimate for in vivo affinity of S(-)-atenolol (4.6x10-8 M) is comparable to literature values for the in vitro affinity in functional assays. In conclusion, a meaningful estimate of in vivo affnity for S(-)-atenolol could be obtained using a mechanism-based pharmacodynamic modelling approach.


Key words: agonist-antagonist interaction model, beta1-adrenoceptor, endogenous agonist, mechanism-based, pharmacokinetic-pharmacodynamic modelling, preclinical




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