Dissertation
Pharmacokinetics, Pharmacodynamics, and Formulation Development of Hydrophobic Xenobiotics
Doctor of Philosophy (PhD), Washington State University
01/2011
Handle:
https://hdl.handle.net/2376/2872
Abstract
Natural products are a reservoir of potential therapeutic agents. One such class of compounds are the polyphenols, small molecular weight compounds found in a range of plant sources that exhibit potent anti-cancer, anti-inflammatory, and anti-oxidant activities. Three polyphenolic compounds were investigated in this thesis including pterostilbene, gnetol, and phloretin all of which are structural analogs of the red wine polyphenol, resveratrol. Novel high performance liquid chromatography (HPLC) or liquid chromatography-mass spectrometry (LC/MS) assays of pterostilbene, gnetol, and phloretin were developed and validated allowing for separation and quantification in biological samples and foodstuffs. Content analysis studies of pterostilbene, gnetol, and phloretin were performed in blueberries, Gnetum Gnemon products, and apples, respectively as well as nutraceutical products. The pharmacokinetics of pterostilbene, gnetol, and phloretin were delineated through intravenous and oral administration in rats. Small structural differences greatly affected their disposition with the compounds generally demonstrating low bioavailabilities, high volumes of distribution, high clearances, short half lives, and elimination via non-renal routes. The in vitro and in vivo pharmacodynamics of pterostilbene, gnetol, and phloretin were elucidated including anti-oxidant, anti-inflammatory, anti-proliferative, anti-adipogenic, and anti-nociceptive activities. All of the polyphenols demonstrated bioactivity with pterostilbene showing the greatest activity especially in inflammation modulation. It appears that 4' hydroxyl moiety is necessary for bioactivity.
In the final section of this thesis, formulation development of hydrophobic chemotherapeutic agents was undertaken. Specifically, three naturally occurring xenobiotics with formulation and tolerability issues due to poor aqueous solubility were investigated: paclitaxel, geldanamycin, and ridaforolimus. These compounds or their prodrug derivatives were encapsulated in amphiphilic block copolymer micelles and their tolerability, pharmacokinetics, and biodistribution investigated. The micelle nanocarriers significantly improved tolerability while augmenting the disposition of the chemotherapeutic. Specifically, the micelle formulations increased area under the curve (AUC) and half life while decreasing clearance and volume of distribution. The increase in serum residence time may allow for accumulation of the nanocarrier into tumor sites through the enhanced permeability and retention effect.
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Details
- Title
- Pharmacokinetics, Pharmacodynamics, and Formulation Development of Hydrophobic Xenobiotics
- Creators
- Connie M. Remsberg
- Contributors
- Neal M Davies (Advisor)Preston K Andrews (Committee Member)Cathy A Elstad (Committee Member)Steven A Martinez (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 290
- Identifiers
- 99900581460001842
- Language
- English
- Resource Type
- Dissertation