用一种新的方法量化人体个体间动力学差异对低剂量氧化罗德利林相对效价的影响。

IF 3 4区 医学 Q1 MEDICINE, LEGAL
F Widjaja-van den Ende, M A J S van Boekel, C Davis, S Wesseling, I M C M Rietjens
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引用次数: 0

摘要

吡咯利西啶生物碱n -氧化物(pa - n -氧化物)在植物和草药食品中占主导地位,食用后转化为吡咯利西啶生物碱(PAs),导致毒性。以riddelliine n -氧化物(RIDO)和riddelliine (RID)为模型化合物,研究了个体间动力学差异对PA- n -氧化物相对PAs (REPPANO to PA)效价值的影响。在30个粪便和25个肝脏S9供体样本的孵育中测量的体外动力学数据显示,个体之间的差异很大,其中个体间的差异是用贝叶斯多水平回归捕获的。将影响PBK模型参数的分布作为输入,进行基于生理的动力学(PBK)建模,并结合蒙特卡罗(MC)模拟,计算prido到RID值的概率分布。在低内剂量水平下,个体间差异被证明是影响prido to RID值的一个因素,而剂量和终点均不起作用。prido与RID值的分布范围为0.71 ~ 0.97(第95百分位),平均值为0.87。所描述的方法可以在低剂量水平下测定个体间的REPPANO与PA值,这在体内实验中无法量化REP值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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 (REPPANO 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 REPRIDO to RID values. At low dose levels, interindividual differences were shown to be a factor that influences the REPRIDO to RID value while neither dose nor endpoint used plays a role. The distribution of the REPRIDO 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 REPPANO to PA values at low dose levels, which are not accessible in in vivo experiments quantifying the REPPANO to PAvalue.

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来源期刊
CiteScore
6.70
自引率
8.80%
发文量
147
审稿时长
58 days
期刊介绍: Regulatory Toxicology and Pharmacology publishes peer reviewed articles that involve the generation, evaluation, and interpretation of experimental animal and human data that are of direct importance and relevance for regulatory authorities with respect to toxicological and pharmacological regulations in society. All peer-reviewed articles that are published should be devoted to improve the protection of human health and environment. Reviews and discussions are welcomed that address legal and/or regulatory decisions with respect to risk assessment and management of toxicological and pharmacological compounds on a scientific basis. It addresses an international readership of scientists, risk assessors and managers, and other professionals active in the field of human and environmental health. Types of peer-reviewed articles published: -Original research articles of relevance for regulatory aspects covering aspects including, but not limited to: 1.Factors influencing human sensitivity 2.Exposure science related to risk assessment 3.Alternative toxicological test methods 4.Frameworks for evaluation and integration of data in regulatory evaluations 5.Harmonization across regulatory agencies 6.Read-across methods and evaluations -Contemporary Reviews on policy related Research issues -Letters to the Editor -Guest Editorials (by Invitation)
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