dc.contributor.advisor |
Wen, J |
en |
dc.contributor.advisor |
Brimble, MA |
en |
dc.contributor.advisor |
Harris, PWR |
en |
dc.contributor.author |
Yin, Naibo |
en |
dc.date.accessioned |
2019-07-08T01:04:55Z |
en |
dc.date.issued |
2019 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/47341 |
en |
dc.description.abstract |
Background and Objectives: Degenerative diseases including cancer, cardiovascular diseases, neurodegenerative diseases, diabetes, rheumatoid arthritis and accelerated aging are a large part of the socioeconomic burden that can influence the lives of anyone at any part of their lives. Many of such degenerative diseases unfortunately have no current cure, leading to the use of prevention strategies. The free radical theory of aging attributes these degenerative diseases to the effects of free radical accumulation and oxidative stress. To combat the negative effects of free radicals, the body produces antioxidants. Glutathione (GSH) is the most important antioxidant in regards to the homeostasis of a body’s overall oxidative stress. However GSH is a peptide, which is easily broken down in the gastrointestinal tract and during first pass metabolism by the hepatic enzyme γ-glutamyl transferase (GGT), resulting in an oral bioavailability of less than 1%. The aim of this project is therefore to produce analogues or pro-drugs of GSH that can significantly boost GSH levels in the body when administered orally. . Results and discussion: The 30 compounds were synthesised with a yield between 6 and 94% with a purity between 75% and 99%. Of the 30 novel compounds, 11 showed resistance towards towards degradation by GGT, 20 have shown loss of efficacy against at least 1 of 3 key enzymes responsible for the efficacy of glutathione, being glutathione S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GPx). Only 2 compounds showed severe cytotoxicity below concentrations of 0.325 mmolL-1, while most compounds displayed no cytotoxicity at the highest concentration range tested (3.25 mmolL-1). Each of the tested compounds showed significantly higher cell viability than the untreated group for cells with induced oxidative stress by irradiation with UVA light. The highest group showed a cell viability of 113.6% ± 5.7 compared to a cell viability of 40.1% ± 4.3 of the untreated control group, indicating complete protection of cells from UVA irradiation in the presence of peptide. The optimal compound was an O-methylated pro-drug of GSH, which displayed a 5.2-fold increase in transport across a Caco-2 monolayer. The optimal pro-drug of glutathione also displayed a 10.8-fold increase in both half-life and oral bioavailability in vivo. An absolute oral bioavailability of 9.7% for GSH was achieved through the use of chemical modification. Conclusion: This project has demonstrated that chemical modification can be utilised to create an oral candidate of GSH. The chemically modified pro-drug displayed improved physiochemical properties and pharmacokinetic parameters, displaying the ability to overcome the physical and biochemical barriers of the gastrointestinal tract. Further chemical modifications to GSH can be made in the future to produce a pro-drug or analogue of GSH with even higher oral bioavailability. The promising results of this project will provide an excellent foundation for the future development of oral GSH. |
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dc.publisher |
ResearchSpace@Auckland |
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dc.relation.ispartof |
PhD Thesis - University of Auckland |
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dc.relation.isreferencedby |
UoA99265158813902091 |
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dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
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dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.rights.uri |
http://creativecommons.org/licenses/by-nc-sa/3.0/nz/ |
en |
dc.title |
Enhancing the Oral Bioavailability of Glutathione (GSH) Using Chemical Modification Approaches |
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dc.type |
Thesis |
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thesis.degree.discipline |
Pharmacy |
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thesis.degree.grantor |
The University of Auckland |
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thesis.degree.level |
Doctoral |
en |
thesis.degree.name |
PhD |
en |
dc.rights.holder |
Copyright: The author |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
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pubs.elements-id |
776148 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Pharmacy |
en |
pubs.record-created-at-source-date |
2019-07-08 |
en |
dc.identifier.wikidata |
Q111963604 |
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