An Overview of Non CYP-Mediated Metabolism Pathways and In Vitro Evaluation Strategies
Presenter: Andrew G. Taylor, Ph.D., Technical Support Manager for Services at XenoTech
Abstract:
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
Continue this Webinar Series:
Dive deeper into the important role of UDP-glucuronosyltransferases (UGTs) in drug metabolism and drug-drug interactions, aldehyde oxidase (AO)–mediated drug metabolism, considerations for in vitro assessment, and concerns about underprediction of drug clearance…
The Role of UGTs in Metabolism & DDI
Considerations for Assessment of AO Metabolism
The Role of SULTs in Metabolism & DDI
About the Presenter:
Dr. Andrew G. Taylor received his Ph.D. from University of California San Diego, Scripps Institution of Oceanography. He joined XenoTech as a research scientist in 2017, serving as a Study Director in nonclinical drug interaction contract studies compliance with Good Laboratory in Practices (GLP), OECD Principles of GLP, &/or Japan MOHW GLP Standards and specializing in drug transport and drug metabolism studies. He became the Technical Support Manager for services in 2020 and provides valuable guidance to ensure research needs are being met.
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