The Importance of Tracking “Missing’ Metabolites: How and Why?
Throughout the course of in-vivo studies, the task of tracking where a drug goes and what it does after entering a living system is, of course, a routine activity for Medicinal Chemists and DMPK Scientists. The data generated will inform the likely outcome of drug dosing in terms of desired efficacy and undesired toxicity, alongside other pharmacologic effects. The key drivers of adverse events are thought to be due to active metabolites, so getting a handle on this early can save a lot of time and money.
This Perspective, which appears to have been a collaborative effort by authors from across a number of large pharmaceutical companies, brings together case studies from where the observed data were far from routine and required problem-solving to elucidate. For example, it begins by pointing out that small-molecule metabolites (–CN, CH2O, CO2, etc.) can be difficult to spot with standard analytical techniques and so creative solutions were described, such as tracing radiolabelled –S14CN (metabolite of -14CN) to distinguish it from endogenous –SCN. Another way in which metabolites can “go missing” is by having a much higher ionisation potential (through, e.g. modulation of pKa) compared to the drug parent, thus causing the MS signal to be weaker than expected.
Other topics covered include (not limited by): limits of detection, metabolite ID/tracking via trial-and-error isotope labelling, identification and quantification of reactive metabolites, accumulation of drug-related entities in certain tissues, targeted covalent inhibitors (TCIs), extra-hepatic metabolism, and the possibility of metabolites that only appear in-vivo.
This is a fantastic resource that will only help to deconvolute complex and unexpected data from DMPK studies.