Scope This study aims to determine if previously developed physiologically‐based kinetic (PBK) model in rat can be modified for senecionine (SEN) and its N‐oxide (SENO), and be used to investigate potential species differences between rat and human in relative potency (REP) of the N‐oxide relative to the parent pyrrolizidine alkaloid (PA). Methods and results In vitro derived kinetic parameters including the apparent maximum velocities (Vmax) and Michaelis–Menten constants (Km) for SENO reduction and SEN clearance are used to define the PBK models. The rat model is validated with published animal data, and the toxicokinetic profiles of SEN from either orally‐administered SENO or SEN are simulated. REP values of SENO relative to SEN amount to 0.84 and 0.89 in rat and human, respectively. Conclusion The REP value can be dose‐ and species‐dependent, with the values for rat and human being comparable at low realistic exposure scenarios. In summary, PBK modeling serves as a valuable New Approach Methodology (NAM) tool for predicting REP values of PA‐N‐oxides and may actually result in more accurate REP values for human risk assessment than what would be defined using in vivo animal experiments.

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.

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