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Updated: Jan 13, 2026

Mass Spectrometry and Luminogenic-based Approaches to Characterize Phase I Metabolic Competency of In Vitro Cell Cultures
Published on: March 28, 2017
Role of metabolites in drug-drug interactions
1Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, United States.
Abstract:
Since the publication of the metabolites in safety testing (MIST) guidance by the US FDA in 2009, there has been continuous interest and expansion in research aimed at predicting and characterizing circulating metabolites. Several systematic reviews and original research articles have been published to assess the role of metabolites in drug-drug interactions. Abundant circulating metabolites have been found to be common with classic cytochrome P450 (CYP) enzyme inhibitors and with new drugs in development. This has raised the need for better tools to predict significant circulating metabolites from preclinical data to streamline metabolite testing. This review summarizes the current recommendations for metabolite testing, evaluates the existing data on reversible and time-dependent inhibition of CYP enzymes by circulating metabolites, and explores the potential inhibition of drug transporters by circulating metabolites. The possible role of metabolites in induction of CYP enzymes is also discussed. The mathematical methods to incorporate multiple precipitants into risk assessment and quantitative prediction methods for inhibition and induction are summarized. Finally, the unique considerations regarding PBPK modeling of metabolites are discussed to highlight potential differences in the metabolite liver concentrations used in static versus more dynamic PBPK prediction methods.
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