Pharmacokinetics of Omega-3 Fatty Acids Esterified in Monoglycerides, Ethyl Esters, or Triglycerides in Humans

Long Chain-Polyunsaturated fatty acids (LC-PUFA) are needed to support normal physiological functions: Unlike saturated and monounsaturated fatty acids, synthesis of eicosapentaenoic acid (EPA, 20:5 omega-3) and docosahexaenoic acid (DHA, 22:6 omega-3) from its omega-3 PUFA precursor, alpha-linolenic acid (18:3 omega-3), is extremely limited in humans. Thus, it is recommended that DHA be obtained from dietary sources such as fish and seafood. Intake of EPA and DHA from fish normally correlates positively with the concentrations of EPA and DHA in plasma. However, recent data suggest that EPA levels are approximately twice higher in plasma lipids of the elderly as compared to young individuals, suggesting that potential alterations in EPA incorporation and utilization occur during aging. Similar results were obtained with a DHA-enriched supplement where the increase of DHA in plasma total lipids was 42% higher in the elderly compared to the young. At sufficient levels of cellular content, the LC-PUFA influence the physical nature of cell membranes and membrane protein-mediated responses, lipid-mediator generation, cell signalling, and gene expression in many different cell types. Through these mechanisms, ARA (arachidonic acid, 20:4 omega-6) and DHA influence both cell and tissue responses to external signals, and thereby their physiology. Therefore, imbalances in LC-PUFA homeostasis potentially induce dysfunctions in the physiology of organs.

Aging of the Canadians and their nutrition: Canada's population is expected to age more rapidly in the coming years. Senior citizens have become more numerous than children in 2015. A major concern about old age, both the individual and society, is a decline in health, especially if this means a loss of self-sufficiency and independence. Increasing research for promoting healthy aging is ongoing but there are physiological modifications occurring during aging that might change bioavailability of LC-PUFA. For instance, intake of EPA and DHA concentrated in fish normally correlates positively with the concentrations of EPA and DHA in plasma. However, recent data from our laboratories suggest that EPA levels are approximately twice higher in plasma lipids of the elderly as compared to young individuals, suggesting that potential alterations in EPA incorporation and utilization occur during aging. DHA response to a DHA-rich supplement was significantly higher in the elderly as compared to the young. While on DHA-rich supplement, ARA was not decreased in the young and the elderly, but similarly to EPA, ARA remained significantly higher in the elderly compared to the young. The investigators also have publish data suggesting that 40 years old is the age where the EPA and DHA levels in the plasma are higher than expected, and this was independent to their dietary omega-3 fatty acid intake. Hence, these results are important indications that the metabolism of LC-PUFA is modified by age and this observation lead to the idea that their uptake and usage by organs and tissue can be compromised.

13C-DHA in humans: Tracing metabolism of carbon 13 (13C)-labelled fatty acids may provide some insight into possible aging-related changes in fatty acid metabolism in humans. The investigators recently used 13C-DHA to trace its metabolism in six young and six elderly participants. The investigators found that, in the elderly, 13C-DHA was 4 times higher in plasma triglycerides and free fatty acids at 4 h post-dose, beta-oxidation was 1.9 times higher whereas apparent retro-conversion of 13C-DHA to other 13C-omega-3 fatty acids was 2.1 times higher 24 h and 7 d after tracer intake compared to the young. Hence, because DHA seems to remain transiently for longer periods of time in the blood of the elderly compared to the young, it may thus indicate that efficiency to remove DHA from the blood is lower in the elderly than in the young, resulting in lower incorporation of DHA in the membrane of cells that serve to initiate signalization. This observation is potentially at the root of altered signalization in the elderly compared to the young.

Bioavailability of EPA and DHA esterified in TG, PL or as an ethyl ester (EE): Most of fish oil supplements on the market are EPA and DHA esterified in TG and to a lower level in EE and PL. There has been a lot of study evaluating whether one form of esterification enhances bioavailability of EPA and DHA. In pharmacology, "Bioavailability" is defined as a subcategory of absorption and it is the portion of the administered dose of a drug or in this case, EPA+DHA that reaches the systemic circulation. By definition, an intravenous drug is 100% bioavailable but when a drug is administered orally, its bioavailability is usually decreased due to incomplete absorption or first-pass metabolism. Hence, in the review paper of Ghasemifard et al., they reviewed 21 papers that evaluated whether omega-3 fatty acid were more bioavailable when given in the form of EE, TG, non-esterified form or as a PL. Four studies were rejected because there were no control group, eight studies were evaluating pharmacokinetics (PK) defined as a follow up between 8 h up to 72 h of a single oral dose of the omega-3 fatty acid product whereas nine studies evaluated the long term intake (pharmacodynamic, PD) of a repeated daily dose of omega-3 fatty acids over a period of 2 weeks and up to 6 months. Although the methodologies of the studies differ, some conclusion about the PK was that bioavailability of EPA+ DHA was higher when given in the forms of non-esterified fatty acid > TG >>> EE. Lower absorption of the EE form might be because pancreatic hydrolysis of EPA and DHA of the EE form compared to the TG form is 10-50 times lower. Hence, the esterification form of omega-3 fatty acids might change their short-term bioavailability and this information is particularly relevant in the context of metabolic diseases that can either affect fat absorption or to an aging population where there are dyslipidemias that might change omega-3 fatty acid bioavailability.

Is MAG-Omega-3 form a better bioavailable source of EPA+DHA?: One study in rats reported bioavailability of DHA esterified in TG, PL or MAG (2-mono-acylglycerol) in plasma, erythrocytes, retina and brain tissue. They reported that after giving DHA in the different forms to rats for 35 days, DHA given in the MAG and PL form were 23-50% more concentrated in plasma total lipids and erythrocytes compared to TG-DHA. In the retina and the brain, DHA increase to the same levels whatsoever esterification form it was provided.