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

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 (V ) and Michaelis-Menten constants (K ) 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.