PHYSIOLOGICAL INDIRECT EFFECT MODELING OF THE ANTILIPOLYTIC EFFECTS OF ADENOSINE A(1)-RECEPTOR AGONISTS

The relationship between blood concentrations of the adenosine Al-rece ptor agonist N-6-(p-sulfophenyl)adenosine (SPA) and its effect on both plasma nonesterified fatty acid (NEFA) and glycerol release was descr ibed on the basis of an integrated pharmacokinetic-pharmacodynamic mod el. An indirect response model rather than a hypothetical ''link'' mod el was used to account for the delayed response. For that purpose an e mpirical solution to the differential equation describing the physiolo gical indirect response model is presented. The model-estimated rate c onstant for the output of the glycerol response was compared to the el imination rate constant after exogenous administration of glycerol. In a crossover designed study, chronically cannulated male Wistar rats w ere subjected to either SPA administration (120 mu g/kg for 15 min) fo r measurement of the effects on glycerol, or glycerol administration f or determination of glycerol pharmncokinetics, Glycerol pharmacokineti cs was determined in the presence of a stable level of SPA (171+/-6 ng /ml) to suppress endogenous glycerol levels completely. The indirect r esponse model adequately described the relationship between SPA concen trations and plasma glycerol levels. The PD parameter estimates for EC 50, E-max, and Hill factor were 23+/-2 ng/ml, 74+/-3% (change from bas eline), and 3.3+/-0.5, respectively. These values were not different f rom those obtained when analyzing the data on basis of the differentia l equation directly. Furthermore the EC50 values for the reduction in glycerol or NEFA levels were identical (23 +/- 2 and 21 +/- 3 ng/ml, r espectively) indicating that both PD endpoints reflect the same physio logical process. The concentration-time profile after administration o f glycerol could be described best on the basis of a biexponential fun ction. The value for k(out) in the PK/PD model (0.19+/-0.03 min(-1)) c orresponded very well to the terminal elimination rate constant determ ined after iv administration of glycerol (0.25 +/- 0.03 min(-1)). In c onclusion, the antilipolytic effects of adenosine A I-receptor agonist s can be described by the indirect suppression model. The rate constan t describing the delay between concentration and glycerol effect was s hown to be a true reflection of the removal of glycerol.