Pharmacokinetic-pharmacodynamic modelling of S(-)-atenolol in rats: reduction of isoprenaline-induced tachycardia as a continuous pharmacodynamic endpoint.
OBJECTIVE
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.


METHODS
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.


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
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.
van Steeg
T J
TJ
Division of Pharmacology, Leiden Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
Freijer
J
J
Danhof
M
M
de Lange
E C M
EC
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000633:toxicity; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000465:Algorithms; D000818:Animals; D001262:Atenolol / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D007545:Isoproterenol / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D008954:Models, Biological; D051381:Rats; D011921:Rats, Inbred WKY; D013237:Stereoisomerism; D013610:Tachycardia / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D001262:Atenolol; D007545:Isoproterenol