Date of Award

2013

Degree Type

Dissertation

Department

Chemistry

First Advisor

Xu, Yan

Subject Headings

Pharmacology, Chemistry, Analytic, Pharmacy -- Research, Liquid chromatography, Mass spectrometry

Abstract

In the anticancer drug discovery and therapy development, it is essential to understand the pharmacological properties of the drugs. Today, pharmaceutical analysis is employed throughout the whole drug discovery and development process. Pharmacokinetic-pharmacodynamic relationships are playing an increasingly important role in decisions on the rational development and use of new drugs and they can provide a detailed knowledge of the mechanism of the drug and a better understanding of the molecular targets on which they act. Due to the significance of pharmacological analysis, sensitive analytical methods are critically needed for pharmacological studies. Therefore, our long-term goal is to provide guidelines in pharmacological studies of the anticancer drugs by quantitatively evaluating the molecular mechanisms of the drugs. In this dissertation, the theory behind the analytical processes and modern bioanalytical technologies, together with their applications in pharmacological studies are discussed in Chapter 1. Dependent on the type of molecules analyzed, different methods were developed to achieve the accurate and reliable detection. Specifically, the development of two HPLC methods with both the UV (Chapter 2) and MS (Chapter 3) detection for analysis of triapine, a ribonucleotide reductase inhibitor, is presented. In the UV method, the chelating nature of triapine was investigated by spectrophotometry, which provides an effective strategy to avoid the unwanted complexation reaction in the quantitation of triapine. An LC-MS/MS method was successfully applied to measurements of patients' samples for pharmacokinetic studies of this drug. Another LCMS/ MS method was developed for quantification of fludarabine incorporated in DNA (Chapter 4). To the best of our knowledge, this is the first LC-MS/MS method developed for quantification of the amount of fludarabine incorporated. The significance of this study is that it provides an accurate method to study the fludarabine pharmacological effect. Moreover

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