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DEVELOPMENT OF LC-MS/MS METHODS FOR QUANTITATIVE ANALYSIS OF PLANT-DERIVED ANTICANCER AGENT AND SYNTHETIC ESTROGEN IN COMPLEX MATRICES

Wabuyele, Simuli Lindah
http://rave.ohiolink.edu/etdc/view?acc_num=csu1400262843

Abstract Details

2013, Doctor of Philosophy in Clinical-Bioanalytical Chemistry, Cleveland State University, College of Sciences and Health Professions.
Quantitative methods of analysis play an important role in early stages of drug discovery and clinical development, as well as, biomonitoring studies of human exposure to endocrine disrupting chemicals (EDCs). It is significant to develop quantitative methods that are highly sensitive, selective and accurate for potential anticancer drugs and EDCs (or their metabolites) in complex matrices considering the fact that; 1) some anticancer agents have a low therapeutic index and have failed in the clinical trials, and 2) the effects of some EDC have been found to occur at very low concentrations. Therefore, such quantitative methods could help predict the absorption, distribution, metabolism and elimination (ADME) of the anticancer agents, and provide a better understanding of the efficacy of the drug and levels of toxicity. In addition, insight on the biotransformation and toxicokinetics of EDCs could be obtained for better assessment of the exposure levels and dosage effect. Currently, the most powerful technique for quantitative analysis is liquid chromatography (LC) method of separation coupled to tandem mass spectrometry (ESI-MS/MS). In this dissertation, a brief overview of the methodology, instrumentation, samples preparation techniques and essential parameters for bioanalytical method validation will be discussed, as well as, the work flow of liquid chromatography tandem mass spectrometry (LC-MS/MS) method development. LC-MS/MS was exploited for quantitative analysis of (-)-Securinine (SE), a plant-derived anticancer agent and Bisphenol A (BPA), a synthetic estrogen. In order to facilitate the pharmaceutical development of SE natural products, i.e., ensure quality, efficacy and safety; a sample preparation method was developed to isolate SE from its natural source; Securinega suffruticosa plant and an LC-MS/MS method was developed and validated to quantify the SE in raw plant material. The method developed was applied to the quantitative analysis of the distribution and levels of SE in different parts of S. suffruticosa plant (i.e., leaves, roots, stems, bark and branches). Furthermore, in order to support the pharmacological studies of SE as a potential anticancer drug, an LC-MS/MS method was developed and validated for quantitative determination of SE in mouse plasma and was applied to the measurement of SE concentrations in a mouse study. Lastly, in order assess human exposure to chemicals that mimic endogenous hormonal action and interfere with the endocrine function (i.e., synthetic estrogens) highly sensitive and accurate techniques are crucial. Due to the prevalence of BPA in laboratory environment and reagents, a metabolite of BPA i.e., Bisphenol A ß-D-glucuronide (BPA-G) was used as a urinary biomarker to assess human exposure to BPA. A stable isotope dilution (SID)-LC-MS/MS method was developed, validated and successfully applied to the measurements of BPA-G in 40 patients’ urine samples.
Yan Xu, PhD (Committee Chair)
Baochuan Guo , PhD (Committee Member)
Xue-Long Sun , PhD (Committee Member)
John Turner , PhD (Committee Member)
Joshua Bagaka’s, PhD (Committee Member)
Chemistry

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Citations

  • Wabuyele, S. L. (2013). DEVELOPMENT OF LC-MS/MS METHODS FOR QUANTITATIVE ANALYSIS OF PLANT-DERIVED ANTICANCER AGENT AND SYNTHETIC ESTROGEN IN COMPLEX MATRICES [Doctoral dissertation, Cleveland State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=csu1400262843

    APA Style (7th edition)

  • Wabuyele, Simuli. DEVELOPMENT OF LC-MS/MS METHODS FOR QUANTITATIVE ANALYSIS OF PLANT-DERIVED ANTICANCER AGENT AND SYNTHETIC ESTROGEN IN COMPLEX MATRICES . 2013. Cleveland State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=csu1400262843.

    MLA Style (8th edition)

  • Wabuyele, Simuli. "DEVELOPMENT OF LC-MS/MS METHODS FOR QUANTITATIVE ANALYSIS OF PLANT-DERIVED ANTICANCER AGENT AND SYNTHETIC ESTROGEN IN COMPLEX MATRICES ." Doctoral dissertation, Cleveland State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=csu1400262843

    Chicago Manual of Style (17th edition)

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© 2013, all rights reserved.
This open access ETD is published by Cleveland State University and OhioLINK.