The Importance of Tracking “Missing” Metabolites: How and Why?

Technologies currently employed to find and identify drug metabolites in complex biological matrices generally yield results that offer a comprehensive picture of the drug metabolite profile. However, drug metabolites can be missed or are captured only late in the drug development process. This could be due to a variety of factors, such as metabolism that results in partial loss of the molecule, covalent bonding to macromolecules, the drug being metabolized in specific human tissues, or poor ionization in a mass spectrometer. These scenarios often draw a great deal of attention from chemistry, safety assessment, and pharmacology. This review will summarize scenarios of missing metabolites, why they are missing, and associated uncovering strategies from deeper investigations. Uncovering previously missed metabolites can have ramifications in drug development with toxicological and pharmacological consequences, and knowledge of these can help in the design of new drugs.