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ARA is an adenosine receptor agonist with high affinity for A1 and A2 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 (Vss: 0.91 L/kg) and short half-life (t1/2: ∼1 hour). The mean percent change in plasma FFA concentrations relative to placebo was best described by an Emax-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 EC50values (%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 A1 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 Kant0 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 Emax-based tolerance model.