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ORIGINAL PAPER

A general model for cell death and biomarker release from injured tissues Jingyun Li1

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Mats O. Karlsson2 • Suchaya Sanhajariya1,3 • Geoffrey K. Isbister3 • Stephen B. Duffull1

Received: 20 March 2020 / Accepted: 18 September 2020 Ó Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract Cellular response to insults may result in the initiation of different cell death processes. For many cases the cell death process will result in an acute release of cellular material that in some circumstances provides valuable information about the process (i.e. may represent a biomarker). The characteristics of the biomarker release is often informative and plays critical roles in clinical practice and toxicology research. The aim of this study is to develop a general, semi-mechanistic model to describe cell turnover and biomarker release by injured tissue that can be used for estimation in pharmacokinetic and (toxicokinetic)-pharmacodynamic studies. The model included three components: (1) natural tissue turnover, (2) biomarker release from cell death and its movement from the cell through the tissue into the blood, (3) different target insult mechanisms of cell death. We applied the general model to biomarker release profiles for four different cell insult causes. Our model simulations showed good agreements with reported data under both delayed release and rapid release cases. Additionally, we illustrate the use of the model to provide different biomarker profiles. We also provided details on interpreting parameters and their values for other researchers to customize its use. In conclusion, our general model provides a basic structure to study the kinetic behaviour of biomarker release and disposition after cellular insult. Keywords Cell death  Necrosis  Toxicology  Tissue homeostasis  Biomarker release  General model  PKPD

Introduction Tissue homeostasis and cell turnover is the result of a balance between cell regeneration and cell death. There are several types of cell death pathways that play important roles in both physiology and pathology, including cellular senescence, programmed cell death (e.g. apoptosis and autophagy), and necrosis. These mechanisms are cellular Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10928-020-09720-1) contains supplementary material, which is available to authorized users. & Jingyun Li [email protected] 1

School of Pharmacy, University of Otago, Dunedin, New Zealand

2

Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden

3

Discipline of Clinical Pharmacology, University of Newcastle, Newcastle, NSW, Australia

responses to intrinsic and extrinsic stress, although are not necessarily independent processes [1–3]. Recent reviews on cellular senescence have highlighted the beneficial roles of senescence in development, physiology and disease, including embryo development, tissue homeostasis, nephrogenesis, wound healing, tissue repair and tumour suppression [