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An Overview of Non CYP Mediated Metabolism Pathways and In Vitro Evaluation Strategies

Presenter: Brian Ogilvie, Ph.D, Vice President of Scientific Consulting at SEKISUI XenoTech


Although cytochrome P450 (CYP)-mediated metabolism continues to be of major importance for a large proportion of small molecule new drug candidates, various methods in recent decades have accelerated the development of drug candidates with significant non CYP-mediated metabolism. Increased interest in these molecules stems from the efforts to develop drug candidates possibly lacking CYP metabolism liability from the drug interactions and toxicity standpoints. Regulatory agencies still have a safety interest in understanding the biochemical pathways involved in the metabolism of these drugs.

In general, uridine diphosphate glucuronosyltransferases (UGTs) are the most common enzymes involved in metabolism after CYP enzymes, followed by numerous hydrolases, carbonyl reductases, aldehyde oxidase and other enzymes. Reaction phenotyping of many of these enzymes is not as straightforward as with CYPs due to their inherent diversity and limited research tools available. With UGTs, commercially available recombinant human preparations are available for the most relevant enzymes, although selective inhibitors may be lacking. In the case of aldehyde oxidase, a recombinant human enzyme and relatively selective inhibitors are available. For hydrolases, carbonyl reductases and other enzymes such as FMO, strategies may rely on the use of various subcellular fractions, plasma, and inhibitors to elucidate a plurality of the enzymes that may contribute to drug metabolism. The complexity of elucidation of non CYP-mediated metabolism is reflected in regulatory safety requirements.

In this webinar, Dr. Brian Ogilvie will discuss strategies to address non-CYP related metabolism questions in your drug’s safety assessment and following the presentation, he will answer follow up questions from the audience.

Key concepts discussed in this webinar will include:

- In vitro approaches to evaluate non-CYP enzyme contribution to new drug candidates

- Case examples

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About the Presenter:

Dr. Brian Ogilvie currently serves as Vice President of Scientific Consulting at SEKISUI XenoTech. Brian obtained his Ph.D. in toxicology from the University of Kansas Medical Center and B.A. in molecular biology from William Jewell College. He joined XenoTech in 1997. From 1999 to 2006 Dr. Ogilvie was the head of the CYP Inhibition Department at SEKISUI XenoTech. Brian is an author or coauthor on over 50 scientific posters, peer-reviewed publications and book chapters on the topics of drug metabolism, transport and drug-drug interactions, and has represented the company as an invited speaker at various drug metabolism conferences. In April 2006, Brian became a member of the SEKISUI XenoTech Consulting Department, in which he participates in drug-drug interaction-related R&D projects and authoring various publications, and also writes expert opinions for consulting clients. As Vice President of Scientific Consulting, Dr. Ogilvie is additionally involved in quality management and strategic planning for the company in scientifically relevant areas.