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Pharmacokinetics of chemopreventive compounds
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Title
Pharmacokinetics of chemopreventive compounds
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ETD_1337
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http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000050477
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eng
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theses
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Topic
Pharmaceutical Science
Subject
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(authority = ETD-LCSH)
Topic
Antioxidants--Physiological effect
Subject
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(authority = ETD-LCSH)
Topic
Pharmacokinetics
Abstract
Cancer claims millions of lives per year. In an effort to find cures to cancer, scientists have turned to chemopreventive compounds that are ingested by humans on a daily basis. Butylated hydroxyanisole (BHA) is a synthetic phenolic antioxidant that is commonly used as a food preservative. Previous studies done on BHA have shown it to exhibit a wide range of biological activities that include protection against acute toxicity of chemicals, modulation of macromolecule synthesis and immune response, induction of phase II detoxifying enzymes, and its potential tumor-promoting activities. Other studies have shown it to have chemopreventive effects. However, little is known about the pharmacokinetics of BHA. The first part of this thesis proposes a study to understand the pharmacokinetics of BHA better. The data showed that BHA followed linear pharmacokinetics within the tested intravenous doses of 10 and 25 mg/kg. The volume of distribution was found to be 1.8 L/kg with a plasma clearance of 60 mL/min/kg and a half-life of 0.7 hr. The bioavailability of BHA at oral doses of 25 mg/kg and 200 mg/kg was found to be 33% and 6%, respectively. The second part of this thesis investigates the effect that Nuclear E2-factor related factor 2 (Nrf2) has on the pharmacokinetics of BHA. Nrf2 belongs to the Cap'n'Collar family of basic region-leucine zipper transcription factors, has been shown to be an essential component of ARE-binding transcriptional machinery. Nrf2 is thought to facilitate the induction of many phase II detoxifying genes. The results of this study showed that Nrf2 deficient mouse had more extended and greater exposure to BHA when the compound is given orally than Nrf2 wild type mice. This suggests that Nrf2 gene may be involved in the metabolism of BHA. The third part of this thesis investigates the usage of nanoparticle drug delivery systems. Previous pharmacokinetics studies done on chemopreventive compound, Dibenzoylmethane (DBM), which is a β-diketone structural analog of curcumin, is a minor constituent of licorice, yield unfavorable results. The bioavailability of DBM when given orally was found to be only 7%. This study was proposed in an effort to increase the bioavailability of DBM. The data showed promising results. When DBM was administered orally to rats in a nanoparticle emulsion, all the pharmacokinetic parameter values increased significantly, compared to the pharmacokinetics parameter values yielded after oral administration of an equal dose in the previous delivery vehicle. The bioavailability increased from 7% to 36% at an oral dose of 250 mg/kg. Similar results were found in a test done on mice.
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xi, 42 p. : ill.
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M.S.
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Includes bibliographical references (p. 41-42)
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by Rachel Tsai-Han Wu
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Wu
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Rachel Tsai-Han
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Rachel Tsai-Han Wu
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Kong
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Tony
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Advisory Committee
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Tony Kong
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Zhou
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Renping
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Advisory Committee
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Renping Zhou
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Minko
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Tamara
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Advisory Committee
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Tamara Minko
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Rutgers University
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Graduate School - New Brunswick
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2008
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2008-10
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xx
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NjNbRU
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Rutgers University Electronic Theses and Dissertations
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ETD
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Graduate School - New Brunswick Electronic Theses and Dissertations
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rucore19991600001
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doi:10.7282/T3P84C6T
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ETD graduate
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The author owns the copyright to this work.
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Open
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Non-exclusive ETD license
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Author Agreement License
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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