The diagnosis of inherited disorders of amino acids (AA) metabolism is usually performed on automated analysers by ion-exchange chromatography and quantification after ninhydrin derivatisation of about 50 different AA. A single run liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for these molecules can be an alternative to this time-consuming technique. The first step of this development is the infusion study of the fragmentation of 79 molecules of biological interest in electrospray ionisation tandem mass spectrometry (ESI-MS/MS), in positive and in negative ionisation mode. Among them, three molecules can be detected only in negative ionisation mode, 38 only in positive mode and 38 in the two modes. All the most abundant fragmentations are presented, with optimisation of the MS/MS parameters. The positive ionisation mode was retained for the simultaneous analysis of 76 molecules. One sensitive and/or specific transition is proposed for the monitoring of each molecule. Improvement in sensitivity of detection was obtained with the use of an acidic mobile phase. Flow injection analysis studies led us to highlight a number of interferences—due to isobaric molecules, to in-source collision-induced dissociation, or to natural isotopic distribution of the elements—which are listed. For a reliable quantification method, these molecules have to be separated by LC before analysis in the tandem mass spectrometer. Ion-pairing reversed-phase liquid chromatography (RPLC) using perfluorinated carboxylic acids as ion-pairing agents has already been found suitable for analysis of AA in MS/MS positive ionisation mode and is under development. Copyright © 2003 John Wiley & Sons, Ltd.
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