LC-MS in drug metabolism studies

Metabolism studies play an important role in dmg discovery and development. The advent of combinatorial dmg synthesis has increased the need for a fast assessment of drag metabolism [1], LC-MS is an important tool in the identification of drag metabolites [2-4], The soft ionization conditions in electrospray ionization (ESI) or atmospheric-pressure chemical ionization (APCI) facilitate the detection of metabolism in biological samples. Many common biotransformation, e.g., oxidation, hydroxy lation, hydrolysis, and reduction, can be detected from just the knowledge of the molecular mass of the metabolites. Further confirmation and/or stractnre elncidation of metabolites is possible using the variety of MS-MS platforms. 

Glucuronic Acid Carboxylic Acids R-COOH - R-COO-Glu Thiols R-SH - R-S-Glu Amines R-NHj R-NH-Glu 

Sulfate + 80 Alcohol R-OH - R-OSO3H Aromatic Amine Ar-NHj Ar-NH-SOjH 

The generation of Phase-I metabolites can be considered as a preparation for the Phase-II metabolism. The detection and identification of Phase-I metabolites is important, because possibly toxic metabolites are formed. Some metabolites are even more active than the dmg itself, either in the action the dmg was administered for or in toxic side effects. Administration of a prodrag with more favourable properties is sometimes performed. The prodrag is rapidly transformed in the actual active substance. Moreover, in quite a number of cases the analytical strategy is directed at identification of the Phase-I metabohtes, even after chemical or enzymatic deconjugation of the Phase-II metabolites. 

The Phase-I biotiansformation reactions often lead to a mass shift relative to the parent componnd (Table 10.1). 

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