In vitro to in vivo acetaminophen hepatotoxicity extrapolation using classical schemes, pharmacodynamic models and a multiscale spatial-temporal liver twin

Frontiers in Bioengineering and Biotechnology

Bioengineering and Biotechnology

Sebastian Zühlke¹  Ute Hofmann²  Selahaddin Sezgin³  Geraldine Cellière⁴  Noemie Boissier⁴  Jules Dichamp⁵  Dirk Drasdo⁵  Joerg Reinders⁶  Jan G. Hengstler⁶  Ahmed Ghallab⁷  Reham Hassan⁷ 

[1] Center for Mass Spectrometry (CMS), Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany;Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, Germany;Faculty of Chemistry and Chemical Biology, TU Dortmund, Dortmund, Germany;Group SIMBIOTX, INRIA Saclay-Île-de-France, Palaiseau, France;Group SIMBIOTX, INRIA Saclay-Île-de-France, Palaiseau, France;Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany;Group MAMBA, INRIA Paris, Paris, France;Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany;Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany;Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt;

关键词: APAP;    in vitro;    acetaminophen;    drug toxicity;    digital twin;    multi-scale;    modeling;    metabolism;   

DOI  :  10.3389/fbioe.2023.1049564

 received in 2022-09-20, accepted in 2023-01-10,  发布年份 2023

来源: Frontiers

【 摘 要 】

In vitro to in vivo extrapolation represents a critical challenge in toxicology. In this paper we explore extrapolation strategies for acetaminophen (APAP) based on mechanistic models, comparing classical (CL) homogeneous compartment pharmacodynamic (PD) models and a spatial-temporal (ST), multiscale digital twin model resolving liver microarchitecture at cellular resolution. The models integrate consensus detoxification reactions in each individual hepatocyte. We study the consequences of the two model types on the extrapolation and show in which cases these models perform better than the classical extrapolation strategy that is based either on the maximal drug concentration (Cmax) or the area under the pharmacokinetic curve (AUC) of the drug blood concentration. We find that an CL-model based on a well-mixed blood compartment is sufficient to correctly predict the in vivo toxicity from in vitro data. However, the ST-model that integrates more experimental information requires a change of at least one parameter to obtain the same prediction, indicating that spatial compartmentalization may indeed be an important factor.

【 授权许可】

Unknown   
Copyright © 2023 Dichamp, Cellière, Ghallab, Hassan, Boissier, Hofmann, Reinders, Sezgin, Zühlke, Hengstler and Drasdo.