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dc.contributor.advisorAlcorn, Jane
dc.contributor.advisorReaney, Martin
dc.creatorGuo, Arka
dc.date.accessioned2020-09-03T22:34:37Z
dc.date.available2020-09-03T22:34:37Z
dc.date.created2020-08
dc.date.issued2020-09-03
dc.date.submittedAugust 2020
dc.identifier.urihttp://hdl.handle.net/10388/12997
dc.description.abstractCardiovascular disease (CVD) is a major contributor to chronic disability and death globally while hypercholesterolemia is a major independent risk factor. Because of adverse effects of currently used CVD drugs (e.g. statins), safer alternatives including natural products might be considered as options for treatment of hypercholesterolemia. Studies have shown that treatment with flaxseed lignan, mainly as secoisolariciresinol diglucoside (SDG), can safely decrease blood cholesterol. However, purified SDG production is expensive; processes that concentrate the natural SDG polymer to 50% or more SDG from flax yield a more cost effective product. Unfortunately, the relative bioavailability of pure SDG and SDG polymer are unknown and the bioactivity of these two forms of SDG are also unknown. This study compared the relative pharmacokinetics of purified SDG and SDG polymer in a single oral dose (40 mg/kg SDG dose) in rat. The concentration of SDG and SDG polymer including secoisolariciresinol (SECO), enterodiol (ED), and enterolactone (ENL) were determined in plasma after administration. The aglycone SECO could only be detected in early plasma samples at 0.25 to 4 h after administration. Unconjugated ED was detected and quantified after 8 (mean ± SD: 3.4 ± 3.3 ng/mL) and 12 h (6.2 ± 3.3 ng/mL) in most subjects, while total ED (unconjugated ED and ED conjugate) was detected in plasma from 2 h to 16 h in most rats. The time of the maximum plasma concentration (Tmax) of total ED in rats fed SDG was 11.7 ± 1.1 h and 10.9 ± 1.9 h for rats fed the SDG polymer. The maximum concentration of total ED (Cmax) for rats fed SDG was 262.2 ± 170.8 ng/mL while for those fed SDG polymer Cmax was 207.2 ± 115.5 ng/mL. Total enterolactone (ENL) was determined for all plasma samples. Tmax of total ENL in rats fed purified SDG was 12.6 ± 1.5 h while for those fed SDG polymer Tmax was 12.7 ± 3 h. Cmax of total ENL in the purified SDG and SDG polymer fed rats was 81.6 ± 23.8 ng/mL, and 65.9 ± 19.6 ng/mL, respectively. The relative bioavailability of total ED and ENL of SDG polymer is 111% and 89%, respectively, when compared to purified SDG. No significant difference in Cmax, Tmax, and AUC of total ED and ENL of purified SDG and SDG polymer was found. In addition, we investigated the effects of chronic daily oral purified SDG (6 mg/kg) or an equivalent dosage of SDG polymer in female Wistar rats fed a 1% cholesterol diet for 1 week before initiation of purified SDG or SDG polymer doses for 23 days. A significant reduction in normalized liver weight was observed in the group treated with purified SDG when compared to high cholesterol control. Both purified SDG and SDG polymer not significantly, but clinically induced a reduction in serum TAG (19% and 15%, respectively) and increase in HDL-C (15% and 24%, respectively). Furthermore, hypercholesterolemic rats given purified SDG or SDG polymer had clinically lower scores in steatosis and non-alcoholic fatty liver disease activity (NAS), when compared to controls. In conclusion, no differences in the absorption kinetics and total exposure of bioactive metabolites was observed between pure SDG and SDG polymer. Moreover, apparent lipid lowering effects were observed following purified SDG and SDG polymer administration, without significant differences between the two groups. Thus, the pharmacokinetic characteristics and hypocholesterolemic effect of SDG polymer warrant its further investigation.
dc.format.mimetypeapplication/pdf
dc.subjectflaxseed lignan
dc.subjectpharmacokinetics
dc.subjectefficacy
dc.subjecthypercholesterolemia
dc.titleComparative oral pharmacokinetics and efficacy of flaxseed lignan-purified SDG and SDG polymer
dc.typeThesis
dc.date.updated2020-09-03T22:34:37Z
thesis.degree.departmentPharmacy and Nutrition
thesis.degree.disciplinePharmacy
thesis.degree.grantorUniversity of Saskatchewan
thesis.degree.levelMasters
thesis.degree.nameMaster of Science (M.Sc.)
dc.type.materialtext
dc.contributor.committeeMemberIldiko, Badea
dc.contributor.committeeMemberChicoine, Alan
dc.contributor.committeeMemberLynn, Weber


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