Considerations for Improving Metabolism Predictions for In Vitro to In Vivo Extrapolation

Marjory Moreau*, Pankajini Mallick, Marci Smeltz, Saad Haider, Chantel I. Nicolas, Salil N. Pendse, Jeremy A. Leonard, Matthew W. Linakis, Patrick D. McMullen, Rebecca A. Clewell, Harvey J. Clewell, Miyoung Yoon

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

11 Scopus citations

Abstract

High-throughput (HT) in vitro to in vivo extrapolation (IVIVE) is an integral component in new approach method (NAM)-based risk assessment paradigms, for rapidly translating in vitro toxicity assay results into the context of in vivo exposure. When coupled with rapid exposure predictions, HT-IVIVE supports the use of HT in vitro assays for risk-based chemical prioritization. However, the reliability of prioritization based on HT bioactivity data and HT-IVIVE can be limited as the domain of applicability of current HT-IVIVE is generally restricted to intrinsic clearance measured primarily in pharmaceutical compounds. Further, current approaches only consider parent chemical toxicity. These limitations occur because current state-of-the-art HT prediction tools for clearance and metabolite kinetics do not provide reliable data to support HT-IVIVE. This paper discusses current challenges in implementation of IVIVE for prioritization and risk assessment and recommends a path forward for addressing the most pressing needs and expanding the utility of IVIVE.

Original languageEnglish (US)
Article number894569
JournalFrontiers in Toxicology
Volume4
DOIs
StatePublished - 2022

Keywords

  • HT-IVIVE
  • in vitro
  • IVIVE
  • metabolism
  • QSAR
  • risk assessment

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
  • Toxicology

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