使用PBPK方法间接模拟餐后肠淋巴对氟茴黄碱的摄取:局限性和意义。

IF 5.5 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Malaz Yousef, Farag E S Mosa, Khaled H Barakat, Neal M Davies, Raimar Löbenberg
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引用次数: 0

摘要

背景/目的:尽管人们认识到肠淋巴通路在药物吸收中的重要性和独特的特点,但其药代动力学模型仍未被广泛探索。本研究旨在通过建立一种基于生理的药代动力学模型(PBPK)来解决这一空白,该模型代表了高脂肪膳食后口服淋巴吸收卤脑碱的情况。方法:使用GastroPlus™9.8.3和已发表的文献数据,对空腹和进食状态下盐茴香碱的吸收、分布、代谢和消除进行建模。由于所使用的软件不直接模拟肠道淋巴运输,因此在餐后ph值的分子动力学模拟下,通过调整参数,如首过代谢、pka驱动的溶解度变化和胆盐介导的溶解作用,间接检测了进食状态下淋巴的参与。结果:药代动力学模型显示,与禁食状态相比,进食状态下盐茴香碱的首过作用有所降低。在禁食状态下,代谢动力学的调整足以构建具有代表性的PBPK模型,而在进食状态下,摄取食物后肠道pH值的变化驱动了盐苯胺的结构重排,因此需要对代谢动力学和其他相关参数进行修改。这些变化通过反映餐后情况的ph中的盐苯胺分子动力学模拟得到证实。结论:本研究强调了通过PBPK模型进一步探索和直接建模肠淋巴摄取的必要性,强调了其在模拟算法中的研究不足。此外,整合具有代表性的物理化学因素对药物的重要性,特别是在餐后条件或脂质制剂中,是显而易见的。总的来说,这些发现有助于在使用事后分析的药物开发中推进预测性监管和开发考虑。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Indirect Modeling of Post-Prandial Intestinal Lymphatic Uptake of Halofantrine Using PBPK Approaches: Limitations and Implications.

Indirect Modeling of Post-Prandial Intestinal Lymphatic Uptake of Halofantrine Using PBPK Approaches: Limitations and Implications.

Indirect Modeling of Post-Prandial Intestinal Lymphatic Uptake of Halofantrine Using PBPK Approaches: Limitations and Implications.

Indirect Modeling of Post-Prandial Intestinal Lymphatic Uptake of Halofantrine Using PBPK Approaches: Limitations and Implications.

Background/Objectives: Despite the recognized importance and distinctive characteristics of the intestinal lymphatic pathway in drug absorption, its pharmacokinetic modeling remains largely unexplored. This study aimed to address this gap by developing a physiologically based pharmacokinetic model (PBPK) to represent the oral lymphatic uptake of halofantrine following a fatty meal. Methods: Using GastroPlus™ 9.8.3 and published literature data, halofantrine absorption, distribution, metabolism, and elimination in both fasting and fed states were modeled. As the used software does not directly simulate intestinal lymphatic transport, lymphatic involvement in the fed state was examined indirectly through parameter adjustments such as first-pass metabolism, pKa-driven solubility changes, and bile-salt-mediated solubilization, with the aid of molecular dynamics simulations under post-prandial pH. Results: The pharmacokinetic models revealed a reduction in the first-pass effect of halofantrine in the fed state compared to that in the fasting state. While adjustments in metabolism kinetics sufficed for constructing a representative PBPK model in the fasting state, capturing the fed-state profile required both modifications to metabolism kinetics and other parameters related to the structural rearrangements of halofantrine driven by the changes in intestinal pH following food intake. These changes were confirmed using molecular dynamics simulations of halofantrine in pHs reflecting the post-prandial conditions. Conclusions: This study underscores the need for further exploration and direct modeling of intestinal lymphatic uptake via PBPK models, highlighting its underexplored status in simulation algorithms. Moreover, the importance of integrating representative physicochemical factors for drugs, particularly in post-prandial conditions or lipid formulations, is evident. Overall, these findings contribute to advancing predictive regulatory and developmental considerations in drug development using post hoc analyses.

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来源期刊
Pharmaceutics
Pharmaceutics Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
7.90
自引率
11.10%
发文量
2379
审稿时长
16.41 days
期刊介绍: Pharmaceutics (ISSN 1999-4923) is an open access journal which provides an advanced forum for the science and technology of pharmaceutics and biopharmaceutics. It publishes reviews, regular research papers, communications,  and short notes. Covered topics include pharmacokinetics, toxicokinetics, pharmacodynamics, pharmacogenetics and pharmacogenomics, and pharmaceutical formulation. Our aim is to encourage scientists to publish their experimental and theoretical details in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
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