High Sensitivity Metabolite Screening with ionKey/MS Using Post-Column Addition

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Angela Doneanu, Jim Murphy, and Paul Rainville
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The importance of metabolite profiling of a new drug is well-recognized. Elucidation of drug metabolite information is crucial due to the fact that drug metabolites can be toxic at certain levels, have a greater pharmacodynamic effect than the parent drug, interfere with concomitant medication, and impact liver function. In drug discovery, liquid chromatography (LC) combined with electrospray ionization (ESI) mass spectrometry (MS) has become the method of choice for obtaining rapid metabolic information due to its ease of use, exceptional selectivity, and applicability, even toward thermally labile polar metabolites, such as glucuronides, sulfates, and glutathione conjugates.

However, in LC/ESI-MS the analyte sensitivity is dependent upon the nature of the analyte, as well as the mobile-phase properties, such as organic solvent and electrolyte contents.

It is accepted that a mobile phase with a higher composition of organic solvents improves the ionization efficiency, especially in the case of negative polarities. However, achieving the desired chromatographic separation of metabolites may require the use of mobile phases that may not be ideal for ESI. Altering solvent properties by post-column addition of a modifier can be an effective technique to improve sensitivity. Post-column addition of an organic modifier stabilizes the spray and allows enhancement of sensitivity without affecting the chromatographic separation.

An attractive aspect of the post-column addition is that the LC part is completely decoupled from the ionization region, which allows the use of an assortment of modifiers.

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