PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF THE ANTI-LIPOLYTIC AND ANTI-KETOTIC EFFECTS OF THE ADENOSINE A(1)-RECEPTOR AGONIST N-6-(P-SULPHOPHENYL)ADENOSINE IN RATS

1 The purpose of this study was to develop and validate an integrated pharmacokinetic-pharmacodynamic model for the anti-lipolytic effects o f the adenosine A(1)-receptor agonist N-6-(p-sulphophenyl)adenosine (S PA). Tissue selectivity of SPA was investigated by quantification of h aemodynamic and anti-lipolytic effects in individual animals. 2 After intravenous infusion of SPA to conscious normotensive Wistar rats, art erial blood samples were drawn for determination of blood SPA concentr ations, plasma non-esterified fatty acid (NEFA) and beta-hydroxybutyra te levels. Blood pressure and heart rate were monitored continuously. 3 The relationship between the SPA concentrations and the NEFA lowerin g effect was described by the indirect suppression model. Administrati on of SPA at different rates and doses (60 mu g kg(-1) in 5 min and 15 min, and 120 mu g kg(-1) in 60 min) led to uniform pharmacodynamic pa rameter estimates. The averaged parameters (mean+/-s.e., n=19) were E- max: -80+/-2% (% change from baseline), EC50: 22+/-2 ng ml(-1), and Hi ll factor: 2.2+/-0.2. 4 In another group, given 400 mu g kg(-1) SPA in 15 min, pharmacodynamic parameters for both heart rate and anti-lipol ytic effect were derived within the same animal. The reduction in hear t rate was directly related to blood concentration on the basis of the sigmoidal E-max model. SPA inhibited lipolysis at concentrations lowe r than those required for an effect on heart rate. The EC50 values (me an+/-s.e., n=6) were 131+/-31 ng ml(-1) and 20+/-3 ng ml(-1) for heart rate and NEFA lowering effect, respectively. 5 In conclusion, the rel ationship between blood SPA concentrations and anti-lipolytic effect w as adequately described by the indirect suppression model. For SPA a 6 fold difference in potency was observed between the effects on heart rate and NEFAs, indicating some degree of tissue selectivity in vivo.