Oral absorption, bioavailability, and uptake routes of omega-3 polyunsaturated fatty acid derived 17(S)-HDHA, 15(S)-HEPE, RvD1 and RvE1 in healthy rats

Abstract Lipid mediators derived from omega-3 polyunsaturated fatty acids (n-3 PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are critical mediators of inflammation. In contrast to EPA and DHA, the bioavailability of their lipid mediator derivatives remains unstudied. Oral, intravenous (IV), and intraduodenal administration of stable isotope labeled n-3 PUFA, and lipid mediators was used to establish their bioavailability, half-lives, and absorption routes in rats. Blood and lymph were analyzed by liquid chromatography–tandem mass spectrometry. Orally administered 17(S)-HDHA-d5, 15(S)-HEPE-d5, and RvD1-d5 were rapidly absorbed into the unesterified plasma pool, reaching peak concentrations within 15 min to 1 h, with a bioavailability of 3–6%. IV administration revealed rapid plasma clearance of n-3 PUFA and administered lipid mediators (half-life ~30 s). Lymph cannulation reduced plasma appearance of 17(S)-HDHA-d5 and 15(S)-HEPE-d5 but not RvD1-d5, indicating structure-dependent changes in absorption via lymphatic or portal routes. These findings demonstrate n-3 PUFA-derived lipid mediators are absorbed following oral intake, providing a foundation for oral delivery.