Influence of Plasma Protein Binding on Pharmacodynamics: Estimation of In Vivo Receptor Affinities of β Blockers Using a New Mechanism-Based PK–PD Modelling Approach

The objective of this investigation was to examine in a systematic manner the influence of plasma protein binding on in vivo pharmacodynamics. Comparative pharmacokinetic–pharmacodynamic studies with four β blockers were performed in conscious rats, using heart rate under isoprenaline-induced tachycardia as a pharmacodynamic endpoint. A recently proposed mechanism-based agonist–antagonist interaction model was used to obtain in vivo estimates of receptor affinities (KB,vivo). These values were compared with in vitro affinities (KB,vitro) on the basis of both total and free drug concentrations. For the total drug concentrations, the KB,vivo estimates were 26, 13, 6.5 and 0.89 nM for S(−)-atenolol, S(−)-propranolol, S(−)-metoprolol and timolol. The KB,vivo estimates on the basis of the free concentrations were 25, 2.0, 5.2 and 0.56 nM, respectively. The KB,vivo–KB,vitro correlation for total drug concentrations clearly deviated from the line of identity, especially for the most highly bound drug S(−)-propranolol (ratio KB,vivo/KB,vitro ∼6.8). For the free drug, the correlation approximated the line of identity. Using this model, for β-blockers the free plasma concentration appears to be the best predictor of in vivo pharmacodynamics. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3816–3828, 2009