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 beta-adrenoceptors (beta-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 i.v. infusion of 5 mg kg(-1) S(-)-atenolol, with or without i.v. infusion of 5 microg 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) (k(eo)) and 0.95+/-0.34 (n). CONCLUSIONS AND IMPLICATIONS: Reduction of heart rate during isoprenaline-induced tachycardia is a reliable pharmacodynamic endpoint for beta-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 beta-blockers.
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 beta-adrenoceptors (beta-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 i.v. infusion of 5 mg kg(-1) S(-)-atenolol, with or without i.v. infusion of 5 microg 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) (k(eo)) and 0.95+/-0.34 (n). CONCLUSIONS AND IMPLICATIONS: Reduction of heart rate during isoprenaline-induced tachycardia is a reliable pharmacodynamic endpoint for beta-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 beta-blockers.
Authors: Klaas P Zuideveld; Piet H Van der Graaf; Donald Newgreen; Richard Thurlow; Nicola Petty; Paul Jordan; Lambertus A Peletier; Meindert Danhof Journal: J Pharmacol Exp Ther Date: 2004-01-08 Impact factor: 4.030
Authors: Christian Höcht; Carla Di Verniero; Javier A W Opezzo; Guillermo F Bramuglia; Carlos A Taira Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2006-05-30 Impact factor: 3.000
Authors: K Nandakumar; S K Bansal; Randhir Singh; S L Bodhankar; D P Jindal; Mohane S Coumar; R Balaraman; S H Bhardwaj Journal: J Pharm Pharmacol Date: 2005-04 Impact factor: 3.765