Details

Autor(en) / Beteiligte

• Widjaja, Frances
• Alhejji, Yasser
• Yangchen, Jamyang
• Wesseling, Sebastiaan
• Rietjens, Ivonne M. C. M.

Titel

Physiologically‐Based Kinetic Modeling Predicts Similar In Vivo Relative Potency of Senecionine N‐Oxide for Rat and Human at Realistic Low Exposure Levels

Ist Teil von

• Molecular nutrition & food research, 2023-02, Vol.67 (4), p.e2200293-n/a

Ort / Verlag

Germany: Wiley Subscription Services, Inc

Erscheinungsjahr

2023

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• 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. The relative potency (REP) of senecionine N‐oxide to senecionine is dose‐ and species‐dependent. The dose dependency is of interest given that the values at low human dietary exposure levels cannot be determined in animal studies where high dose levels are used. Also, REP values for human can only be obtained with New Approach Methodology.