Cardiac enzymes such as cytochrome P450 2J2 (CYP2J2) metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic acids (EETs), which in turn are metabolized by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs). As EETs and less potent DHETs exhibit cardioprotective and vasoprotective functions, optimum levels of cardiac EETs are paramount in cardiac homeostasis. Previously, we demonstrated that dronedarone, amiodarone and their main metabolites, namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA), potently inhibit human cardiac CYP2J2-mediated astemizole metabolism in vitro. In this study, we investigated the inhibition of recombinant human CYP450 enzymes (rhCYP2J2, rhCYP2C8, rhCYP2C9)-mediated AA metabolism and human recombinant sEH (rhsEH)-mediated EET metabolism by dronedarone, amiodarone, NDBD and NDEA. A static model describing sequential metabolism was further developed to predict the aggregate effect of dual-inhibition of rhCYP2J2 and rhsEH on the fold-of 14,15-EET level Symbol. Dronedarone, amiodarone and NDBD inhibit rhCYP2J2-mediated metabolism of AA to 14,15-EET with Ki values of 3.25, 5.48, 1.39 μM respectively. Additionally, dronedarone, amiodarone, NDBD and NDEA inhibit rhsEH-mediated metabolism of 14,15-EET to 14,15-DHET with Ki values of 5.10, 13.08, 2.04, 1.88 μM respectively. Based on static sequential metabolism modelling, dronedarone (Symbol = 0.85), amiodarone (Symbol = 0.48) and NDBD (Symbol = 0.76) were predicted to decrease cardiac 14,15-EET level whereas NDEA (Symbol > 35.5) was predicted to elevate it. Based on our novel findings, we postulate the differential cardiac exacerbation potential of dronedarone and amiodarone is partly associated with their differential inhibition potencies of cardiac CYP2J2 and sEH.