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

Abstract

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.

Toxins in Botanical Drugs and Plant-derived Food and Feed – from Science to Regulation: A Workshop Review

“…It was observed that the PBK-model-based predicted REP PANO to PA values for riddelliine N -oxide 36 and senecionine N -oxide 37 in rats, calculated based on plasma AUC PA levels (method 1), are close to in vivo -derived REP PANO to PA values ( Fig. 7 ) 36 , 37 . Although the kinetic constants for PANO reduction and PA clearance in rats and humans were different, the two REP PANO to PA values at low dose levels were found to be similar for both species 37 .…”

“…It was observed that the PBK-model-based predicted REP PANO to PA values for riddelliine N-oxide [36] and senecionine N-oxide [37] in rats, calculated based on plasma AUC PA levels (method 1), are close to in vivo-derived REP PANO to PA values (▶ Fig. 7) [36,37].…”

“…In a first method, the REP PANO to PA values can be determined based on the ratio between the area under the curve (AUC) for the parent PA upon dosing either the PANO (plasma AUC PA (dose PANO)) or an equimolar dose of the PA (plasma AUC PA (dose PA (▶ Fig. 6, method 1) [36,37]. In a second method, REP PANO to PA values can be calculated based on the ratio of the amount of pyrrole-protein adducts upon dosing either PANO or an equimolar dose of PA (▶ Fig.…”

“…The PBK model contained in silico -derived parameters and in vitro experimentally determined kinetic parameters and considered not only dose levels as high as the ones used in animal studies but also those that are low and more realistic for human exposure. The power of PBK modeling is the ability to predict REP PANO to PA values at realistic low dose levels, which would be less accessible in in vivo studies, and also to predict data for humans by defining a PBK model for the PANOs in humans 37 . In vitro studies on 7-GS-DHP formation allowed definition of the kinetic parameters to include this metabolic step in the PBK model and enable calculation of the REP PANO to PA value by method 2 38 , 39 .…”

“…7 ) 36 , 37 . Although the kinetic constants for PANO reduction and PA clearance in rats and humans were different, the two REP PANO to PA values at low dose levels were found to be similar for both species 37 . Moreover, it appeared that the REP PANO to PA values were dose- as well as endpoint-dependent at the oral dose ranges that were examined in this study (approximately 1 to 200 µmol · kg −1 bw) ( Fig.…”