RESUMO
RPR749 and its methylated metabolite are orally active and selective adenosine A(1) agonists that can inhibit lipolysis and lower plasma triglyceride levels in a variety of animal models. RPR749 also appears to lower free fatty acid (FFA) and insulin levels and may have additional lipid-modifying effects. This double-blind, single increasing-dose, placebo-controlled, parallel group, randomized study, the first done in humans, evaluated the safety, pharmacokinetics, and pharmacodynamics (effect on FFA) after a single oral dose of up to 200 mg RPR749 or placebo. Six parallel groups of 8 healthy men (6 active and 2 placebo/group) were enrolled in the study. Plasma samples were collected for up to 72 hours post-dose. RPR749 and its metabolite RPR772 concentrations were measured by a validated LC/MS/MS method with a minimal quantifiable limit of 1 ng/mL. RPR749 was safe and well tolerated as a single oral dose up to 200 mg. The mean plasma concentrations of RPR749 were approximately 30-fold higher than the mean RPR772 plasma concentrations. The mean terminal half-life (t(1/2)) of RPR749 and RPR772 were similar (approximately 16.4 hours). Mean values for serum insulin, triglycerides, glycerol, and blood glucose remained within normal ranges. Mean FFA concentrations in serum decreased in all treatment groups with the maximal decrease in the 200-mg dose group. In conclusion, RPR749 has the ability to reduce circulating levels of FFA that can be related to plasma RPR749 concentrations and thus possesses pharmacological properties that may be beneficial in treating coronary artery diseases and hyperlipidemia.