CPSA 2011

Science and Technology Coming Together to Make a Difference

October 3 - 6, 2011
Bucks County Sheraton Hotel
Langhorne, PA

Program Abstract

Keynote

Liquid Chromatography-Mass Spectrometry in Pharmacology Research and its Transition to Clinical Applications

Ian A. Blair
Centers for Cancer Pharmacology and Excellence in Environmental Toxicology
University of Pennsylvania
Philadelphia, PA 19104

Pharmacological research has become highly dependent upon liquid chromatography (LC-MS)-based methodologies over the last decade and many of the discoveries that have been made are now being translated or are in the process of being translated into clinical applications. Of critical importance has been the incorporation of stable isotope dilution methodology, which has made it possible to obtain highly reproducible and accurate quantification of structurally diverse compounds in complex biological fluids. This has made it possible to devise methodology for the identification and quantification of novel lipids, lipid-modified DNA-adducts, oxidized DNA-bases, tobacco carcinogens, glutathione-adducts, and serum proteins and steroids. LC-electron capture atmospheric pressure chemical ionization (ECAPCI)/MS has proved to be particularly useful for the characterization of potent endogenous anti-proliferative lipids, the analysis of DNA-adducts, and the chiral analyses of trace amounts of biomolecules such as eicosanoids. More recently, the development of pre-ionized derivatives that can be analyzed using LC positive ion electrospray ionization/MS has improved detection sensitivity still further. Thus, the N-propyl derivative was employed for the tobacco-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), the Girard P derivative for estrone and its metabolites, and the N-methyl-pyridinium-sulfonate derivative for estradiol and its metabolites. Validated stable isotope dilution liquid-chromatography-mass spectrometry assays were then developed for urinary NNAL and serum estrogen biomarkers with limits of detection in the amol/mL range. This made it possible for the first time to quantify the anti-proliferative 2-methoxyestradiol in serum samples from postmenopausal women and to show that estradiol oxidation to estrone was dysregulated in the cigarette smokers. Other applications of LC-MS techniques that have been designed for specific applications in pharmacology research will be discussed together with an appraisal of their potential utility as biomarkers of disease.

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