Physiological indirect effect modeling of the antilipolytic effects of adenosine A1-receptor agonists

The relationship between blood concentrations of the adenosine A1-receptor agonist N6-(p-sulfophenyl) adenosine (SPA) and its effect on both plasma nonesterified fatty acid (NEFA) and glycerol release was described on the basis of an integrated pharmacokinetic-pharmacodynamic model. An indirect response model rather than a hypothetical "link" model was used to account for the delayed response. For that purpose an empirical solution to the differential equation describing the physiological indirect response model is presented. The model-estimated rate constant for the output of the glycerol response was compared to the elimination rate constant after exogenous administration of glycerol. In a crossover designed study, chronically cannulated male Wistar rats were subjected to either SPA administration (120 microgram/kg for 15 min) for measurement of the effects on glycerol, or glycerol administration for determination of glycerol pharmacokinetics. Glycerol pharmacokinetics was determined in the presence of a stable level of SPA (171 +/- 6 ng/ml) to suppress endogenous glycerol levels completely. The indirect response model adequately described the relationship between SPA concentrations and plasma glycerol levels. The PD parameter estimates for EC50, EMAX, and Hill factor were 23 +/- 2 ng/ml, 74 +/- 3% (change from baseline), and 3.3 +/- 0.5, respectively. These values were not different from those obtained when analyzing the data on basis of the differential equation directly. Furthermore, the EC50 values for the reduction in glycerol or NEFA levels were identical (23 +/- 2 and 21 +/- 3 ng/ml, respectively) indicating that both PD endpoints reflect the same physiological process. The concentration-time profile after administration of glycerol could be described best on the basis of a biexponential function. The value for kout in the PK/PD model (0.19 +/- 0.03 min-1) corresponded very well to the terminal elimination rate constant determined after i.v. administration of glycerol (0.25 +/- 0.03 min-1). In conclusion, the antilipolytic effects of adenosine A1-receptor agonists can be described by the indirect suppression model. The rate constant describing the delay between concentration and glycerol effect was shown to be a true reflection of the removal of glycerol.