The increasingly popular science of metabonomics has the potential to significantly improve the drug discovery and development process. This discipline involves the monitoring of the changes in the endogenous metabolism profile due to disease state or as a response to a toxic insult. To date the majority of the published metabonomics studies have employed proton NMR, however recently there has been increased interest in the use of LC/MS and in particular LC/MS-TOF, with exact mass, for metabonomics. The data generated has shown that LC/MS-TOF is can be either a viable alternative to proton NMR or can be used as a complementary technique. However there are still significan t challenges that face the metabolism scientist from an LC/MS point of view, three of the most critical are; the resolution/detection of all of the components in the sample throughput and the ability to deal polar analytes.

HPLC has been a steadily evolving science since the development of spherical particles back in the early 1980’s, with most improvements been merely incremental. Recently, however Dr Jorgenson at UNC has pioneered the use of very small particles and very high pressure, >20000psi to effect extremely high efficiency separations. This represents a significant step change in the performance of liquid chromatography. The ability to employ these very small porous particles <2um at pressure in excess of 10,000 psi has recently been made available to the general scientist by Waters Corporation as UPLC™. This technique has immediate impact on LC/MS the extra chromatographic efficiency gives rise to sharper peaks, thus more resolution, more sensitivity (>3 fold in MS) and for throughput. The over effect of this extra performance finds its greatest impact in the analysis of complex mixtures, were resolution is essential for good results. In this paper we will show how this technology has been applied to metabonomic samples, both urine and plasma and has resulted in superior throughput with run times in the order of 2 minutes, 3-5 fold increase in MS sensitivity, superior spectral data and more biomarkers detected.