Pharmacokinetic‐pharmacodynamic modelling of S(−)‐atenolol in rats: reduction of isoprenaline‐induced tachycardia as a continuous pharmacodynamic endpoint

Background and purpose: For development of mechanism‐based pharmacokinetic‐pharmacodynamic (PK‐PD) models, continuous recording of drug effects is essential. We therefore explored the use of isoprenaline in the continuous measurement of the cardiovascular effects of antagonists of β‐adrenoceptors (β‐blockers). The aim was to validate heart rate as a pharmacodynamic endpoint under continuous isoprenaline‐induced tachycardia by means of PK‐PD modelling of S(−)‐atenolol. Experimental approach: Groups of WKY rats received a 15 min iv infusion of 5 mg kg−1 S(−)‐atenolol, with or without iv infusion of 5 μg kg−1 h−1 isoprenaline. Heart rate was continuously monitored and blood samples were taken. Key results: A three‐compartment model best described the pharmacokinetics of S(−)‐atenolol. The PK–PD relationship was described by a sigmoid Emax model and an effect compartment was used to resolve the observed hysteresis. In the group without isoprenaline, the variability in heart rate (30 b.p.m.) approximated the maximal effect (Emax=43±18 b.p.m.), leaving the parameter estimate of potency (EC50=28±27 ng ml−1) unreliable. Both precise and reliable parameter estimates were obtained during isoprenaline‐induced tachycardia: 517±13 b.p.m. (E0), 168±15 b.p.m. (Emax), 49±14 ng ml−1 (EC50), 0.042±0.012 min−1 (keo) and 0.95±0.34 (n). Conclusions and implications: Reduction of heart rate during isoprenaline‐induced tachycardia is a reliable pharmacodynamic endpoint for β‐blockers in vivo in rats. Consequently this experimental approach will be used to investigate the relationship between drug characteristics and in vivo effects of different β‐blockers. British Journal of Pharmacology (2007) 151, 356–366; doi:10.1038/sj.bjp.0707234