Metabolism of Ethyl Eicosapentaenoate (EPA-E) in Rats and Effect of Its Metabolites on Ellagic Acid-Induced Thrombus Formation in the Stenosed Femoral Artery of Rabbits

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The metabolism of ethyl eicosapentaenoate (EPA-E) was investigated in rats in vivo and in vitro with uniformly labelled ¹⁴C-EPA-E, and the antithrombotic properties of major metabolites of EPA-E in rabbits were examined.When ¹⁴C-EPA-E was administered orally to rats, eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) were identified in the liver as metabolites of EPA-E. These metabolites were incorporated mainly into phospholipids and triglycerides, and were found at the C-2 position of phospholipids and the C-1 and/or C-3 positions of triglycerides.When ¹⁴C-EPA coenzyme A (¹⁴C-EPA-CoA) was incubated with intact mitochondria, ¹⁴CO₂ was released and chain-shortened metabolites were detected by radio-high performance liquid chromatography. When ¹⁴C-EPA-CoA was incubated with intact peroxisomes, chain-shortened metabolites were detected as in the case of mitochondria.When potassium eicosapentaenoate (¹⁴C-EPA·K) was incubated with microsomes, DPA and DHA were produced as a result of chain elongation and subsequent desaturation reactions. When ¹⁴C-EPA-CoA was incubated with intact peroxisomes, DPA was produced in the presence of malonyl-CoA as a cofactor.EPA-E significantly decreased the incidence of thrombus formation and also decreased the length of thrombi in rabbits. Major metabolites of EPA-E, such as EPA, DPA and DHA, moderately decreased the incidence of thrombus formation.