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
Year: 2024
Type: article
Abstract: Pyrrolizidine alkaloid 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 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 (95th 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 PANO to PA value. • The metabolism of riddelliine and its N-oxide in human individuals is variable. • The consequences for the relative potency of riddelliine N-oxide are quantified. • At low doses, the relative potency is still affected by kinetic variability.
Authors: F. Widjaja-van den Ende, M.A.J.S. van Boekel, C. Davis, S. Wesseling, I.M.C.M. Rietjens
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,950
OpenAlex ID: W4405624083