Pharmacokinetic and pharmacodynamic studies on flaxseed lignans
| dc.contributor.advisor | Alcorn, Jane | en_US |
| dc.contributor.advisor | Krol, Edward S. | en_US |
| dc.contributor.committeeMember | Zello, Gordon | en_US |
| dc.contributor.committeeMember | Muir, Alister | en_US |
| dc.contributor.committeeMember | Bandy, Brian | en_US |
| dc.contributor.committeeMember | Mansell, Kerry | en_US |
| dc.contributor.committeeMember | Dobson, Roy | en_US |
| dc.creator | Mukker, Jatinder | en_US |
| dc.date.accessioned | 2013-08-15T17:20:19Z | |
| dc.date.available | 2013-08-15T17:20:19Z | |
| dc.date.created | 2013-01 | en_US |
| dc.date.issued | 2013-02-06 | en_US |
| dc.date.submitted | January 2013 | en_US |
| dc.description.abstract | Natural Health Products (NHPs) are regulated and require safety and efficacy information for their approval into the Canadian market. Flaxseed lignans are NHPs with putative health benefits in a number of chronic diseases. In the flaxseed the principal lignan is secoisolariciresinol diglucoside (SDG). After oral consumption SDG is converted into its aglycone secoisolarisiresinol (SECO) and subsequently into mammalian lignans (enterodiol (ED) and enterolactone (EL)) in the presence of gastrointestinal microflora. In my Ph.D. research, I conducted a series of in vitro and in vivo PK studies to enable the design of prospective safety and efficacy studies of lignans. In vitro PK studies in the Caco-2 cell monolayer suggest that SDG has poor intestinal permeation and intestinal conjugation characteristics (glucuronidation and sulphation); however, SECO, ED and EL undergo passive permeation and extensive conjugation (SECO<ED<EL) by Caco-2 cells. Single oral and intravenous dose pharmacokinetics in male Wistar rats showed that these lignans exhibit high volumes of distribution, high systemic clearance values, and short half-lives. EL was fatal to the rats at the given intravenous and oral doses while SDG was not orally bioavailable and may not likely be the bioactive lignan form. I investigated the effect of acute SDG and chronic BeneFlax oral administration in blunting the postprandial hyperglycemia in healthy and streptozotocin induced male Wistar type II diabetic rats, respectively; however, my pilot study failed to show any change in postprandial blood glucose levels. Further, I conducted selective cytotoxicity evaluations in prostate and breast cancer cell lines. Only EL caused selective cytotoxicity of breast and prostate cancer cells with IC50 values that may be physiologically achievable. To elucidate the mechanism of action, I tested concentration and time dependent effects of EL on various enzymes and transcription factors of fatty acid metabolism at mRNA and protein levels in cancer (PC-3) and normal (RWPE-1) prostate cell lines. mRNA and protein expression analysis showed a concentration and time dependent inhibition of fatty acid synthase (FAS) and suggested that EL may inhibit FAS to show anti-proliferative effect on prostate cancer. The pharmacokinetic characteristics and pharmacodynamics properties of flaxseed lignans warrant their further investigation. | en_US |
| dc.identifier.uri | http://hdl.handle.net/10388/ETD-2013-01-895 | en_US |
| dc.language.iso | eng | en_US |
| dc.subject | Flaxseed | en_US |
| dc.subject | Lignans, Pharmacokinetics, Pharmacodynamics | en_US |
| dc.title | Pharmacokinetic and pharmacodynamic studies on flaxseed lignans | en_US |
| dc.type.genre | Thesis | en_US |
| dc.type.material | text | en_US |
| thesis.degree.department | Pharmacy and Nutrition | en_US |
| thesis.degree.discipline | Pharmacy | en_US |
| thesis.degree.grantor | University of Saskatchewan | en_US |
| thesis.degree.level | Doctoral | en_US |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) | en_US |