Recent developments in predicting CYP-independent metabolism

Abstract

As lead optimization efforts have successfully reduced metabolic liabilities due to cytochrome P450 (CYP)-mediated metabolism, there has been an increase in the frequency of involvement of non-CYP enzymes in the metabolism of investigational compounds. Although there have been numerous notable advancements in the characterization of non-CYP enzymes with respect to their localization, reaction mechanisms, species differences and identification of typical substrates, accurate prediction of non-CYP-mediated clearance, with a particular emphasis with the difficulties in accounting for any extrahepatic contributions, remains a challenge. The current manuscript comprehensively summarizes the recent advancements in the prediction of drug metabolism and the in vitro to in vitro extrapolation of clearance for substrates of non-CYP drug metabolizing enzymes.

Keywords:

• Non-CYP enzymes; alcohol and aldehyde dehydrogenase; aldehyde oxidase; carboxylesterase; flavin-containing monooxygenase; glutathione-S-transferase; monoamine oxidase; sulfotransferase; UDP glucuronosyltransferase; xanthine oxidase

Acknowledgements

The authors would like to thank the International Society for the Study of Xenobiotics (ISSX) for the platform and resources provided to us new investigators in the development of this manuscript. We would especially like to acknowledge Zoë Fuller of ISSX and the ISSX New Investigators Group for her unwavering support and perpetual encouragement. The authors thank Dr. Anna Radominska-Pandya of Drug Metabolism and Reviews for her enthusiasm in supporting the development of new investigators in the field of drug metabolism. Finally, we would like to acknowledge the immense efforts of the numerous new investigators involved in this project (Schleiff and Sodhi 2021) who collaborated collaboratively composed a number of articles that will guide both new and established investigators alike.

Disclosure statement

The authors declare no conflict of interest. The research conducted and opinions described in this manuscript are their own and are not influenced by the authors’ respective employers.

Additional information

Funding

Nikhilesh V. Dhuria is supported by the Department of Pharmaceutical Sciences, University of Nebraska Medical Center. Mary A. Schleiff is supported by NIGMS grant T32 GM106999. Jasleen K. Sodhi was supported in part by an American Foundation for Pharmaceutical Education Predoctoral Fellowship, NIGMS grant R25 GM56847 and a Louis Zeh Fellowship.