MODELING OF THE PHARMACODYNAMIC INTERACTION OF AN A(1) ADENOSINE RECEPTOR AGONIST AND ANTAGONIST IN-VIVO - N-6-CYCLOPENTYLADENOSINE AND 8-CYCLOPENTYLTHEOPHYLLINE
S. Appel et al., MODELING OF THE PHARMACODYNAMIC INTERACTION OF AN A(1) ADENOSINE RECEPTOR AGONIST AND ANTAGONIST IN-VIVO - N-6-CYCLOPENTYLADENOSINE AND 8-CYCLOPENTYLTHEOPHYLLINE, British Journal of Pharmacology, 115(7), 1995, pp. 1253-1259
1 The purpose of this investigation was to develop a pharmacokinetic-p
harmacodynamic model for the interaction between an adenosine A(1) rec
eptor agonist and antagonist in vivo. The adenosine A(1) receptor agon
ist, N-6-cyclopentyladenosine (CPA) and the antagonist, 8-cyclopentylt
heophylline (CPT) were used as model drugs. The CPA-induced reduction
in mean arterial pressure and heart rate were used as measurements of
effect. 2 Four groups of eight rats each received 200 mu g kg(-1) of C
PA i.v. in 5 min during a steady-state infusion of CPT at a rate of 0,
57, 114 or 228 mu g kg(-1)h(-1). The haemodynamic parameters were con
tinuously measured and frequent blood samples were taken to determine
the pharmacokinetics of the drugs. 3 CPT had no influence on the pharm
acokinetics of CPA and the baseline values of the haemodynamic variabl
es. Furthermore, no clear antagonism by CPT was observed of the CPA-in
duced reduction in mean arterial pressure. However, CPT antagonized th
e effect on heart rate, and with increasing CPT concentrations, a para
llel shift of the CPA concentration-effect relationship to the right w
as observed. 4 An agonist-antagonist interaction model was used to cha
racterize the interaction quantitatively. On the basis of this model,
the pharmacodynamic parameters of both CPA and CPT could be estimated.
For CPA the values were (mean +/- s.e.): E(max) = 198 +/- 11 b.p.m.,
EC(50) = 2.1 +/- 0.7 ng ml(-1), Hill factor = 2.3 +/- 0.6 and for CPT:
ECS, = 3.7 +/- 0.3 ng ml(-1) and Hill factor = 3.1 +/- 0.1. 5 It is c
oncluded that the competitive agonist-antagonist interaction model may
be of value to characterize quantitatively the pharmacodynamic intera
ctions between adenosine A(1) receptor ligands in vivo.