The Role of Kinetics as Key Determinant in Toxicity of Pyrrolizidine Alkaloids and Their N-Oxides

Frances Widjaja, Yasser Alhejji, Ivonne M.C.M. Rietjens*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)


Pyrrolizidine alkaloids (PAs) are a large group of plant constituents of which especially the 1,2- unsaturated PAs raise a concern because of their liver toxicity and potential genotoxic carcinogenicity. This toxicity of PAs depends on their kinetics. Differences in absorption, distribution, metabolism, and excretion (ADME) characteristics of PAs may substantially alter the relative toxicity of PAs. As a result, kinetics will also affect relative potency (REP) values. The present review summarizes the current state-of-the art on PA kinetics and resulting consequences for toxicity and illustrates how physiologically-based kinetic (PBK) modelling can be applied to take kinetics into account when defining the relative differences in toxicity between PAs in the in vivo situation. We conclude that toxicokinetics play an important role in the overall toxicity of pyrrolizidine alkaloids. and that kinetics should therefore be considered when defining REP values for combined risk assessment. New approach methodologies (NAMs) can be of use to quantify these kinetic differences between PAs and their N-oxides, thus contributing to the 3Rs (Replacement, Reduction and Refinement) in animal studies.

Original languageEnglish
Pages (from-to)130-143
JournalPlanta Medica
Issue number02
Early online date5 Nov 2021
Publication statusPublished - Feb 2022


  • Physiologically-based kinetic (PBK) models
  • pyrrolizidine alkaloid N-oxides
  • pyrrolizidine alkaloids
  • relative potency (REP) value
  • Toxicokinetics


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