Modelling of the pharmacodynamic interaction of an A1 adenosine receptor agonist and antagonist in vivo: N6-cyclopentyladenosine and 8-cyclopentyltheophylline.
1. The purpose of this investigation was to develop a pharmacokinetic-pharmacodynamic model for the interaction between an adenosine A1 receptor agonist and antagonist in vivo. The adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA) and the antagonist, 8-cyclopentyltheophylline (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 micrograms kg-1 of CPA i.v. in 5 min during a steady-state infusion of CPT at a rate of 0, 57, 114 or 228 micrograms kg-1 h-1. The haemodynamic parameters were continuously measured and frequent blood samples were taken to determine the pharmacokinetics of the drugs. 3. CPT had no influence on the pharmacokinetics of CPA and the baseline values of the haemodynamic variables. Furthermore, no clear antagonism by CPT was observed of the CPA-induced reduction in mean arterial pressure. However, CPT antagonized the effect on heart rate, and with increasing CPT concentrations, a parallel shift of the CPA concentration-effect relationship to the right was observed. 4. An agonist-antagonist interaction model was used to characterize 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.): Emax = 198 +/- 11 b.p.m., EC50 = 2.1 +/- 0.7 ng ml-1, Hill factor = 2.3 +/- 0.6 and for CPT: EC50 = 3.7 +/- 0.3 ng ml-1 and Hill factor = 3.1 +/- 0.1. 5. It is concluded that the competitive agonist-antagonist interaction model may be of value to characterize quantitatively the pharmacodynamic interactions between adenosine A1 receptor ligands in vivo.
Appel
S
S
Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, University of Leiden, The Netherlands.
Mathôt
R A
RA
Langemeijer
M W
MW
IJzerman
A P
AP
Danhof
M
M
D000241:Adenosine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008956:Models, Chemical; D011485:Protein Binding; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000187:drug effects*; D013806:Theophylline / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology
D001798:Blood Proteins; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; C053907:8-cyclopentyl-1,3-dimethylxanthine; C048599:N(6)-cyclopentyladenosine; D013806:Theophylline; D000241:Adenosine