The past decade of Genentech experience in elucidation of novel reaction mechanisms in drug metabolism

Drug metabolism is critical to many aspects of drug safety and efficacy. Thus, understanding the various intricacies of drug metabolism helps to avoid possible pitfalls and contributes to drug design during the discovery stage and to drug characterization during the development stage. Drug metabolis...

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Bibliographic Details
Published in:Medicinal chemistry research 2023-09, Vol.32 (9), p.2016-2033
Main Authors: Khojasteh, Cyrus, Sodhi, Jasleen K., Halladay, Jason, Zhang, Donglu
Format: Article
Language:English
Subjects:
Aldehyde oxidase
Aldehydes
Biochemistry
Biomedical and Life Sciences
Biomedicine
Bioorganic Chemistry
Case studies
Cytochrome
Cytochrome P450
Cytochromes P450
Design of experiments
Drug development
Drug metabolism
Enzyme kinetics
Inorganic Chemistry
Medicinal Chemistry
Metabolism
Metabolites
Pharmacology/Toxicology
Pharmacovigilance
Reaction mechanisms
Review Article
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Summary:Drug metabolism is critical to many aspects of drug safety and efficacy. Thus, understanding the various intricacies of drug metabolism helps to avoid possible pitfalls and contributes to drug design during the discovery stage and to drug characterization during the development stage. Drug metabolism expertise was mainly taught at the universities and prominent professors have contributed to the field and here, we like to acknowledge Professor Thomas Baillie contribution to the field. Over the years, we have deployed our learnings in both drug discovery and development at Genentech. Here, we describe case studies from novel reaction mechanisms to novel types of metabolites. Taken together, we describe our lessons in a manner that allows the reader to understand the significance of the lessons and the thinking behind the experimental design. Here, we describe 10 case studies that highlight our experience in the past decade with the first 5 case studies capturing non-cytochrome P450 enzymatic reactions such as the discovery of a novel hydrolytic reaction by aldehyde oxidase (Case Study 1). The remaining 5 case studies describe cytochrome P450-derived reactions including various types of cytochrome P450-mediated reactions that resulted in ring formation or cleavage (Case Studies 6–9). The last case study (Case Study 10), emphasizes the importance of exploring ways to understand binding and enzyme kinetics, and explores co-incubation of 1-aminobenzotriazole (ABT) with warfarin in CYP2C9 metabolism.
ISSN:1054-2523
1554-8120
DOI:10.1007/s00044-023-03128-5