PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF THE CARDIOVASCULAR EFFECTS OF R-N-6-PHENYLISOPROPYLADENOSINE AND S-N-6-PHENYLISOPROPYLADENOSINEIN CONSCIOUS NORMOTENSIVE RATS

Recently, the commercially available adenosine receptor agonist S-N-6- phenylisopropyladenosine (S-PIA) has been demonstrated to be contamina ted with the more potent R-diastereomer. The potency of S-PIA may ther efore have been overestimated in previously published in vivo studies. Our objective was to determine the potency of both diastereomers in c onscious normotensive rats by using an integrated pharmacokinetic-phar macodynamic model. In a cross-over designed study, the animals receive d i.v. infusions of 177 mu g/kg (0.51 mu mol/kg) R-N-6-phenylisopropyl adenosine (R-PIA) and 4000 mu g/kg (11.6 mu mol/kg) S-PIA. The infusio n of S-PIA corresponded to a simultaneous administration of 3823 mu g/ kg (11.1 mu mol/kg) and 177 mu g/kg (0.51 mu mol/kg) of the S- and R-d iastereomer, respectively. During the experiment, time courses of hear t rate and blood pressure were recorded continuously. Serial arterial blood samples were collected and concentrations were determined by usi ng a stereoselective high-performance liquid chromatography assay. Aft er administration of R-PIA, the individual concentration-effect relati onships could be quantified by the sigmoidal E(max) model, yielding an EC(50) value of 24 +/- 3 ng/ml for the reduction in heart rate (mean +/- S.E., n = 12). After administration of S-PIA, a similar EC(50) val ue was obtained when heart rate was correlated to concentrations of R- PIA. Modelling of the concentration-effect data according to a competi tive interaction model did not yield pharmacodynamic parameter estimat es for S-PIA. In conclusion, the cardiovascular effects observed after infusion of S-PIA may be attributed entirely to the presence of R-PIA .