CC BY-NC-ND 4.0 · Planta Med 2022; 88(02): 130-143
DOI: 10.1055/a-1582-9794
Focus Issue Pyrrolizidine Alkaloids

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

1   Division of Toxicology, Wageningen University and Research, The Netherlands
Yasser Alhejji
1   Division of Toxicology, Wageningen University and Research, The Netherlands
2   Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
Ivonne M. C. M. Rietjens
1   Division of Toxicology, Wageningen University and Research, The Netherlands
› Author Affiliations
Supported by: Qassim University 35796


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.

Supporting Information

Publication History

Received: 13 April 2021

Accepted after revision: 09 August 2021

Article published online:
05 November 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (

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