While cytochrome P450 (CYP)-mediated metabolism continues to be of primary concern for the majority of new small molecule drug candidates, efforts to develop compounds that do not have CYP metabolism liability from drug-drug interaction (DDI) and toxicity standpoints have resulted in an increasing number of compounds with significant non CYP-mediated metabolism. However, reaction phenotyping of these enzymes is not always as straightforward as with CYPs because of their diversity and test system limitations. Regardless, regulatory agencies have a safety interest in understanding the metabolism pathways of new drug candidates, and the complexity of elucidating non CYP-mediated metabolism is reflected in their safety requirements.

In April of 2021, Dr. Brian Ogilvie, Vice President of Scientific Consulting at BioIVT, provided an overview of these pathways including a discussion of regulatory interest, case examples, in vitro reaction phenotyping approaches and strategies to evaluate non-CYP enzyme contribution to new drug candidates. This article encompasses the key takeaways from his presentation.