Quantifying the effect of human interindividual kinetic differences on the relative potency value for riddelliine N-oxide at low dose levels by a new approach methodology

F Widjaja; M A J S van Boekel; C Davis; S Wesseling; I M C M Rietjens

doi:10.1016/j.yrtph.2024.105767

Quantifying the effect of human interindividual kinetic differences on the relative potency value for riddelliine N-oxide at low dose levels by a new approach methodology

Regul Toxicol Pharmacol. 2024 Dec 20:105767. doi: 10.1016/j.yrtph.2024.105767. Online ahead of print.

Authors

F Widjaja¹, M A J S van Boekel², C Davis³, S Wesseling⁴, I M C M Rietjens⁴

Affiliations

¹ Division of Toxicology, Wageningen University, PO Box 8000, 6700 EA Wageningen, the Netherlands. Electronic address: [email protected].
² Food Quality and Design, Wageningen University, PO Box 8129, 6700 EV Wageningen, the Netherlands.
³ Daiichi Sankyo, Inc. 211 Mt. Airy Rd. Basking Ridge, NJ, 07920, USA.
⁴ Division of Toxicology, Wageningen University, PO Box 8000, 6700 EA Wageningen, the Netherlands.

PMID: 39710333
DOI: 10.1016/j.yrtph.2024.105767

Abstract

Pyrrolizidine alkaloids N-oxides (PA-N-oxides) are predominant in plants and herbal foods, and are converted to pyrrolizidine alkaloids (PAs) upon consumption, leading to toxicity. The effect of interindividual kinetic differences on the relative potency values of PA-N-oxides compared to their PAs (REP_{PANO to PA}) was studied, with riddelliine N-oxide (RIDO) and riddelliine (RID) as model compounds. In vitro kinetic data measured in incubations with 30 fecal and 25 liver S9 donor samples showed high variation across individuals, where the interindividual variability was captured with Bayesian multilevel regression. The distributions of influential PBK model parameters were used as input for physiologically based kinetic (PBK) modeling combined with Monte Carlo (MC) simulations to calculate the probability distribution of REP_{RIDO to RID} values. At low internal dose levels, interindividual differences were shown to be a factor that influences the REP_{RIDO to RID} value while neither dose nor endpoint used plays a role. The distribution of the REP_{RIDO to RID} value ranged from 0.71 to 0.97 (95^th percentile) with a mean value of 0.87. The approach described enables determination of interindividual REP_{PANO to PA} values at low dose levels, which are not accessible in in vivo experiments quantifying the REP value.