A physiologically based pharmacokinetic (PBPK) model to align dosimetry of the isobutyl metabolic series in rats and humans.

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology Pub Date : 2025-12-01 Epub Date: 2025-07-26 DOI:10.1016/j.yrtph.2025.105914

Jordan N Smith, Kimberly J Tyrrell, Karl K Weitz, Willem Faber

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引用次数: 0

Abstract

We developed a physiologically based pharmacokinetic (PBPK) model in rats and humans for the isobutyl metabolic series, which includes isobutyl acetate, isobutanol, isobutyraldehyde, and isobutyric acid. Given chemical similarities, we used a previously developed PBPK model for the propyl metabolic series as a framework to create the isobutyl PBPK model. To support model development, we measured in vitro metabolism of isobutyl acetate in rat and human blood and liver S9 fractions. Our findings indicated that humans exhibited faster isobutyl acetate hydrolysis in liver S9 fractions compared to rats, while hydrolysis rates in blood were similar between the two species. Experiments involving closed chamber exposures of rats to isobutyl acetate or isobutanol revealed higher isobutanol concentrations in blood compared to other isobutyl compounds. Using these data to parameterize the model, the PBPK model accurately simulated available time-course concentrations of isobutyl compounds in blood of rats and humans. The isobutyl PBPK model enables comparisons of internal dose metrics across various isobutyl compound exposures and species and allows for calculation of equivalent external exposures that result in the same dose metric. Regulators can employ this PBPK model to predict and align internal dose metrics of isobutyl compounds for risk assessment purposes.

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基于生理的药代动力学（PBPK）模型来校准大鼠和人异丁基代谢系列的剂量测定。

我们针对异丁基代谢系列（包括醋酸异丁酯、异丁醇、异丁醛和异丁酸）在大鼠和人体内建立了基于生理学的药代动力学（PBPK）模型。考虑到化学相似性，我们使用先前开发的丙基代谢系列PBPK模型作为框架来创建异丁基PBPK模型。为了支持模型的建立，我们测量了大鼠和人血液和肝脏S9组分中乙酸异丁酯的体外代谢。我们的研究结果表明，与大鼠相比，人类肝脏S9组分中乙酸异丁酯的水解速度更快，而血液中的水解速率在两种物种之间相似。在封闭的室内实验中，将大鼠暴露于醋酸异丁酯或异丁醇中，结果显示，与其他异丁基化合物相比，血液中异丁醇的浓度更高。利用这些数据参数化模型，PBPK模型准确地模拟了大鼠和人血液中异丁基化合物的可用时间过程浓度。异丁基PBPK模型能够比较各种异丁基化合物暴露和种类之间的内部剂量度量，并允许计算产生相同剂量度量的等效外部暴露。监管机构可以使用该PBPK模型来预测和调整异丁基化合物的内部剂量指标，以进行风险评估。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Regulatory Toxicology and Pharmacology 医学-毒理学

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)