TIME-COURSE OF ACTION OF 3 ADENOSINE A(1) RECEPTOR AGONISTS WITH DIFFERING LIPOPHILICITY IN RATS - COMPARISON OF PHARMACOKINETIC, HEMODYNAMIC AND EEG EFFECTS
Ea. Vanschaick et al., TIME-COURSE OF ACTION OF 3 ADENOSINE A(1) RECEPTOR AGONISTS WITH DIFFERING LIPOPHILICITY IN RATS - COMPARISON OF PHARMACOKINETIC, HEMODYNAMIC AND EEG EFFECTS, Naunyn-Schmiedeberg's archives of pharmacology, 356(6), 1997, pp. 827-837
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.