Abstract
Secoisolariciresinol diglucoside (SDG) is the principal lignan of flaxseed and precursor of its aglycone, secoisolariciresinol (SECO), and the mammalian lignans enterolactone (EL) and enterodiol (ED), the putative bioactive forms of oral administration of SDG. SDG is present in the seed hull as an ester-linked polymer. Although extraction and purification of SDG monomer is costly, the use of naturally occurring SDG in polymer form may offer a more economical approach for delivery of this precursor. The extent of SDG release from the polymer and subsequent bioavailability of SDG metabolites are unknown. To understand the relative bioavailability of SDG polymer, this study examined the comparative bioavailability of enriched SDG and SDG polymer in rats after a single oral SDG equivalent dose (40 mg/kg). A validated LC-MS/MS method quantified SDG and its metabolites in rat plasma following serial blood collections. SDG remained undetectable in rat plasma samples. Unconjugated SECO was detected in plasma after 0.25 h. Unconjugated ED was observed after 8 h (3.4 ± 3.3 ng/mL) and 12 h (6.2 ± 3.3 ng/mL) for enriched SDG and SDG polymer, respectively. Total (conjugated and unconjugated) ED and EL resulting from enriched SDG and SDG polymer reached similar maximal concentrations between 11 and 12 h and demonstrated similar total body exposures (AUC values). These data suggest a similar pharmacokinetic profile between the enriched and polymer form of SDG, providing support for the use of SDG polymer as a more economical precursor for SECO, ED, and EL in applications of chronic disease management.
Link to Full Text
Key Points
How lignans become systemically available when present within the ester-linked polymer is not completely known. This study conducted a comparative oral bioavailability assessment between enriched SDG and SDG polymer in female rats. Similar pharmacokinetic (PK) profiles of the SDG metabolites will provide important lignans in chronic diseases such as hypercholesterolemia.
Lignans in different product forms have demonstrated the ability to reduce blood cholesterol levels and degree of hepatic lipidosis.
Dosage and efficacy of SDG polymer is dependent upon the efficiency from which SDG is released from the polymer matrix. In this study, comparison of the relative oral bioavailability of SDG polymer to enriched SDG demonstrated no statistically significant differences in exposure metrics (i.e., AUC, Cmax). Nonetheless, before SDG polymer can be considered an effective alternative to enriched SDG for therapeutic applications such as hypercholesterolemia, further studies in human participants are warranted. Considerable interindividual variability was observed in plasma concentration versus time profiles. No significant differences were observed in the mean Cmax, tmax, and AUC between total ED and total EL, therefore demonstrating comparable relative bioavailability of ED and EL between SDG and SDG polymer. The bioavailability of SDG metabolites can be influenced by their physicochemical properties, interindividual differences in intestinal microflora, and extent of first-pass metabolism.
Once released from the polymer, these factors should have equivalent effects on SDG and SDG metabolite absorption characteristics. Incomplete hydrolysis of SDG polymer can contribute to decreased relative oral bioavailability; however, the lack of statistical significance in the rate and extent of ED and EL absorption suggests efficient hydrolysis of dietary SDG polymer.