TIME-COURSE OF ACTION OF 3 ADENOSINE A(1) RECEPTOR AGONISTS WITH DIFFERING LIPOPHILICITY IN RATS - COMPARISON OF PHARMACOKINETIC, HEMODYNAMIC AND EEG EFFECTS

In this study we investigated the relationship between the pharmacokin etics and the cardiovascular and electroencephalogram (EEG) effects of three adenosine agonists with differing lipophilicity. Conscious norm otensive rats received either 600 mu g/kg N-6-(p-sulphophenyl) adenosi ne (SPA), 200 mu g/kg N-6-cyclopentyladenosine (CPA) or 600 mu g/kg 1- deaza-2-chloro-N-6-cyclopentyladenosine (DCCA) in a 5-min intravenous infusion. Changes in haemodynamics and EEG were monitored in conjuncti on with arterial blood sampling to determine blood concentrations of t he compounds. The three adenosine agonists showed large differences in pharmacokinetic properties, resulting in terminal half-lives of 66 +/ - 10, 8.2 +/- 0.4 and 24 +/- 1 min (mean +/- SEM) for SPA, CPA, and DC CA respectively. SPA had a significantly lower blood clearance relativ e to CPA and DCCA, whereas DCCA had the lamest volume of distribution and degree of plasma protein binding. The relationship between concent ration and heart rate could be described adequately by the sigmoidal E -max model. For SPA, CPA, and DCCA the EC50 values based on free drug concentrations were 423 +/- 92, 1.8 +/- 0.4 and 9.5 +/- 1.1 nM respect ively. These in vivo values correlated closely with the affinity of th e compounds for the adenosine A(1), receptor as determined in radiolig and binding studies, with corresponding K-i values of 1410 +/- 220, 4. 7 +/- 0.6 and 102 +/- 74 nM (mean +/- SEM) respectively. In the EEG, o nly CPA produced a small decrease in the amplitude of beta waves. This study demonstrates that the three adenosine analogues have large diff erences in pharmacokinetics, which complicates comparison of their car diovascular and central responses simply on the basis of dose. The app lication of an integrated PK/PD approach permits estimates of potency and activity which are independent of underlying dose and pharmacokine tics.