MODELING OF THE PHARMACODYNAMIC INTERACTION OF AN A(1) ADENOSINE RECEPTOR AGONIST AND ANTAGONIST IN-VIVO - N-6-CYCLOPENTYLADENOSINE AND 8-CYCLOPENTYLTHEOPHYLLINE

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.