The single-dose kinetics of [1–14C]-labelled EPA and DHA, administered to male rats as TAG, phosphatidylcholine (PC), and lyso-phosphatidylcholine (LPC), is structurally similar across lipid forms and can be described using the same compartmental models

Abstract

To investigate the systemic kinetics of EPA and DHA across different lipid classes, male rats were administered [1–¹⁴C]-radiolabelled EPA and DHA as triglycerides (TAG), phosphatidylcholine (PC), or lyso-phosphatidylcholine (LPC) by gavage. LPC was also administered intravenously. Plasma and whole blood concentration-time profiles were recorded from 0 to 168 hours, while cumulative radioactivity in expired air, faeces, and urine was recorded for up to 336 hours.

Non-compartmental analysis and compartmental modelling demonstrated overall first-order radiotracer kinetics for both fatty acids, with comparable terminal half-lives. The primary difference was in maximum concentration (Cmax ((µg-eq/g)/(mg/kg)): DHA = 0.18± 0.089, EPA = 0.24± 0.103; P < 0.0001). Between TAG and PC, only time to maximum concentration (Tmax (h)) differed (PC = 3.23 ± 0.94, TAG = 2.55 ± 0.77; P = 0.0004). LPC showed significant differences from TAG and PC in area under the curve (AUC0-inf), Cmax, Tmax, and total clearance (CL/F (mL/(kg h))). Cumulative radioactivity levels in expired air and faeces were consistent with blood and plasma kinetics.

As suggested by early-phase (0 to 48 hours) radioactivity accumulation, which deviated from first-order behaviour, TAG and PC, but not LPC, exhibited some faecal loss without systemic absorption.

The compartmental models developed performed equally well for radiolabelled EPA and DHA, regardless of whether administered as TAG, PC, or LPC. The model can be adapted to handle non-zero endogenous baselines and was successfully applied to non-radiolabelled EPA, docosapentaenoic acid (DPA), and DHA, quantified via LC-MS/MS. These models can be applied to both radioactive and stable isotopes and adapted to include organ-specific kinetics, as well as those of EPA, DPA, and DHA in other species, including humans.