Pharmacokinetic-pharmacodynamic modeling of the antilipolytic effects of an adenosine receptor agonist in healthy volunteers.

ARA is an adenosine receptor agonist with high affinity for A 1 and A 2 receptors, which are involved in regulation of free fatty acid (FFA) production. Two parallel groups of 13 healthy males were enrolled in a Phase I study to evaluate the pharmacokinetics of this compound and to characterize its effect on plasma FFA concentrations following administration of a single 6-hour intravenous infusion of ARA or placebo. ARA plasma concentrations were measured by a validated high-performance liquid chromatographic method (fluorescence detection). ARA is a highly cleared compound (Cl: 0.79 L/h/kg) with a modest volume of distribution (V ss : 0.91 L/kg) and short half-life (t 1/2 : ∼ 1 hour). The mean percent change in plasma FFA concentrations relative to placebo was best described by an E max -based tolerance model, in which a hypothetical metabolite/antagonist was used to describe the apparent development of tolerance to the suppressive effects of ARA on FFA levels, The EC 50 values (%RSE of estimate) for ARA and the hypothetical antagonist were 17.0 (5.4) and 15.6 (12.8) ng/mL, respectively. The use of adenosine A 1 agonists as antilipolytic drugs may be restricted due to the potential development of tolerance, and thus a period of abstinence from the agonist may be required before the response of FFA returns to pretolerant conditions. In the case of ARA, the value of 0.33 h -1 for K ant0 indicates that a period of approximately 11 hours should suffice. In agreement with preclinical data previously reported in literature, the present study provides evidence that desensitization of adenosine receptor-mediated inhibition of lipolysis may occur in humans. In conclusion, the ability of ARA to reduce circulating levels of FFA can be related to plasma ARA concentrations using a modified E max -based tolerance model.