Construction of a physiologically based pharmacokinetic model of paclobutrazol and exposure estimation in the human body

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY Toxicology Pub Date : 2024-05-23 DOI:10.1016/j.tox.2024.153841

Xiaomeng Li , Tingting Lian , Buda Su, Hui Liu, Yuming Wang, Xiaoyan Wu, Junjie He, Yue Wang, Yanyan Xu, Shenshen Yang, Yubo Li

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Abstract

Paclobutrazol (PBZ) is a plant growth regulator that can delay plant growth and improve plant resistance and yield. Although it has been widely used in the growth of medicinal plants, human beings may take it by taking traditional Chinese medicine. There are no published studies on PBZ exposure in humans or standardized limits for PBZ in medicinal plants. We measured the solubility, oil–water partition coefficient (logP), and pharmacokinetics of PBZ in rats and established a physiologically based pharmacokinetic (PBPK) model of PBZ in rats. This was followed by extrapolation to healthy Chinese adult males as a theoretical foundation for future risk assessment of PBZ. The results showed that PBZ had low solubility and high fat solubility. Pharmacokinetic experiments showed that PBZ was absorbed rapidly but eliminated slowly in rats. On this basis, the rat PBPK model was successfully constructed and extrapolated to healthy Chinese adult males to predict the plasma concentration–time curve and exposure of PBZ in humans. The construction of the PBPK model of PBZ in this study facilitates the determination of the standard formulation limits and risk assessment of PBZ residues in medicinal plants.

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构建基于生理学的帕克鲁曲唑药代动力学模型并估算人体暴露量

多效唑（PBZ）是一种植物生长调节剂，可延缓植物生长，提高植物抗性和产量。虽然它被广泛用于药用植物的生长，但人类也可能通过服用中药而摄入它。目前还没有关于人类接触 PBZ 或药用植物中 PBZ 标准限值的公开研究。我们测定了 PBZ 在大鼠体内的溶解度、油水分配系数（logP）和药代动力学，并建立了 PBZ 在大鼠体内的生理药代动力学（PBPK）模型。随后，将该模型推断到健康的中国成年男性身上，作为未来 PBZ 风险评估的理论基础。结果表明，PBZ 的溶解度低，脂溶解度高。药代动力学实验表明，PBZ 在大鼠体内吸收迅速，但消除缓慢。在此基础上，成功构建了大鼠 PBPK 模型，并将该模型外推至健康的中国成年男性，以预测 PBZ 在人体内的血浆浓度-时间曲线和暴露量。本研究建立的 PBZ PBPK 模型有助于确定药用植物中 PBZ 残留的标准制剂限量和风险评估。

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文献相关原料

公司名称	产品信息	其他信息	采购帮参考价格
上海源叶	PBZ standard	≥95%

来源期刊

Toxicology 医学-毒理学

CiteScore

7.80

自引率

4.40%

发文量

222

审稿时长

23 days

期刊介绍： Toxicology is an international, peer-reviewed journal that publishes only the highest quality original scientific research and critical reviews describing hypothesis-based investigations into mechanisms of toxicity associated with exposures to xenobiotic chemicals, particularly as it relates to human health. In this respect "mechanisms" is defined on both the macro (e.g. physiological, biological, kinetic, species, sex, etc.) and molecular (genomic, transcriptomic, metabolic, etc.) scale. Emphasis is placed on findings that identify novel hazards and that can be extrapolated to exposures and mechanisms that are relevant to estimating human risk. Toxicology also publishes brief communications, personal commentaries and opinion articles, as well as concise expert reviews on contemporary topics. All research and review articles published in Toxicology are subject to rigorous peer review. Authors are asked to contact the Editor-in-Chief prior to submitting review articles or commentaries for consideration for publication in Toxicology.