(R)-CE3F4, a specific inhibitor of EPAC1 (exchange protein directly activated by cAMP type 1), has been demonstrated in vitro and in vivo to reduce hypertrophic signaling contributing to heart failure or to control arrhythmia and has shown promise as a drug candidate. However, (R)-CE3F4 exhibits poor solubility in aqueous media and has shown sensitivity to enzyme hydrolysis in plasma. To overcome these issues, the drug was entrapped in liposomes and lipid nanocapsules. Both systems considerably increased the drug apparent solubility in aqueous media. Among these nanocarriers, lipid nanocapsules offered significant protection in vitro against enzymatic degradation by increasing the (R)-CE3F4 apparent half-life from around 40 min to 6 h. Pharmacokinetics and biodistribution of (R)-CE3F4 radiolabeled or not were studied in healthy C57BL/6 mice. The non-encapsulated 3H-CE3F4 showed a very rapid distribution outside the blood compartment. Similar results were observed when using nanocarriers together with a fast dissociation of 3H-CE3F4 from nanocapsules simultaneously labeled with 14C. Thus, essential preclinical information on CE3F4 fate has been obtained, as well as the impact of its formulation using lipid-based nanocarriers.