Oral Pharmacokinetics of Enriched Secoisolariciresinol Diglucoside and Its Polymer in Rats

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.

Hypocholesterolemic Efficacy of Secoisolariciresinol Diglucoside and Its Polymer in Rat

“…The hypocholesterolemic and hypolipidemic effects of HMG have also been observed in rabbits 46 and in humans. 47,48 Although the combined hypocholesterolemic effects of HMG and SDG are currently unknown, pharmacokinetic 45 and efficacy (this study) studies suggest that HMG may not significantly increase the hypocholesterolemic effects of SDG polymer compared to enriched SDG. Together, the similarities in the hypocholesterolemic and pharmacokinetic effects of enriched SDG and SDG polymer suggest that SDG polymer may serve as a more economical alternative for treatment of hypercholesterolemia without the need for SDG enrichment.…”

“…44 The absorption kinetics (e.g., relative bioavailability) and total exposure to bioactive metabolites (e.g., ENL, EDL, and SECO) are similar for treatments that include SDG polymer and enriched SDG. 45 Although, how these lignans become systematically available when present as an ester-linked polymer is not completely known. The hypocholesterolemic and hypolipidemic effects of HMG have also been observed in rabbits 46 and in humans.…”

“…These hypocholesterolemic and antiatherogenic effects are attributed to the antioxidant properties of SDG, its aglycone, secoisolariciresinol (SECO), and their mammalian lignan metabolites, enterodiol (EDL) and enteroloactone (ENL), − and are associated with metabolic syndrome . The absorption kinetics (e.g., relative bioavailability) and total exposure to bioactive metabolites (e.g., ENL, EDL, and SECO) are similar for treatments that include SDG polymer and enriched SDG . Although, how these lignans become systematically available when present as an ester-linked polymer is not completely known.…”

Anticancer potential of flaxseed lignans, their metabolites and synthetic counterparts in relation with molecular targets: current challenges and future perspectives

“…After oral ingestion of FLs, the intestinal bacteria and enzymes take action to hydrolyze the FLs into corresponding aglycones, which have more potential to pass through the intestinal epithelia. 7 Particularly, SDG has poor bioavailability due to the attached sugar moiety which blocks its absorption within the gut epithelial layers 7 where it undergoes bacterial fermentation by β-glucosidase, thus the glucose component of SDG is converted to its aglycones, secoisolariciresinol (SECO). Furthermore, bacterial dihydroxylation and demethylation reactions further convert SECO into enterodiol (ED), which subsequently gets oxidized by microbes to produce enterolactone (EL).…”

Beyond Bread and Beer: Value-Added Products from Wheat

“…Wheat β-glucans, lignans, and phytosterols have been investigated as treatments for hypercholesterolemia and cardiovascular disease [58][59][60]. Importantly, a major lignan in wheat bran was identified to be secoisolariciresinol diglucoside (SDG), which is known to be converted into the mammalian lignans enterodiol and enterolactone by intestinal microflora [61,62]. Wheat also contains lariciresinol diglucoside.…”