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11 Bioequivalence of the Precursors Alfa-Linolenic Acids (LNA) and Eicosapentaenoic Acid (EPA) in the Synthesis of Docosahexaenoic Acid (DHA) Using a Multi-Compartmental Model with Stable Isotope Methodology

Introduction: Docosahexaenoic acid (22:6n3; DHA), an essential fatty acid (EFA), is a major component of the nervous system and is required for optimal neuronal function. Human infants can synthesize DHA from dietary alpha-linolenic acid (18:3n3;LNA) with eicosapentaenoate (20:5n3; EPA) and docosapentaenoate (22:5n3; DPA) as intermediates. It is of interest then to determine whether LNA or its partially metabolized form, EPA, would be a better substrate to support DHA biosynthesis. Previously we have used isotopic ratios to report a higher DHA formation from LNA(x5) compared to EPA.Objective: To determine kinetic parameters that reflect the flow of tracer in different compartments using a multi-compartmental physiologic model, as an indirect indicator of the n-3 metabolic pathway fatty acids occurring in the liver.Subjects and Methods: Term neonates (n=11) were administrated a single oral dose of 20 mg of d5-LNA and 2 mg of 13C-EPA per kg of BW. Blood was then sampled at 0, 4, 8, 24, 48, 96, 168 hr after administration, and, tracers were simultaneously detected in plasma using CG/EM. Physiologic compartmental model, developed in the WInSAAM software, was used to determine the coefficients of the in vivo rate constants of the labeled n-3 fatty acids in plasma. A greater rate constant coefficient for the conversion of d5 DPA to d5 -22:6n3 (0.05 hr-1) than for 13C-DPA to 13C-DHA (0.014 hr-1) was determined from the model calculations on seven infants.Results: This resulted in an hourly synthetic rate of 47 nmol (or 16 mcg) for the LNA-derived DHA compared to 17 nmol (or 5.9 mcg) for the EPA-derived DHA (P=0.041). However, half-lives were the same for both labeled-22:6n3 species.Conclusion: Compartmental modeling is a useful tool for calculating biosynthetic rate parameters that are needed for determining n-3 fatty acid substrate utilization for DHA supply.