Towards improved PBTK modelling for organic (ionizable) chemicals

Montage by UFZ Leipzig Image of 4OR0 (Bujacz, A., Zielinski, K., Sekula, B. (2014) Proteins 82: 2199-2208 ) created with NGL Viewer (AS Rose, AR Bradley, Y Valasatava, JM Duarte, A Prlic and PW Rose. Web-based molecular graphics for large complexes. ACM Proceedings of the 21st International Conference on Web3D Technology (Web3D '16): 185-186, 2016. doi:10.1145/2945292.2945324;AS Rose and PW Hildebrand. NGL Viewer: a web application for molecular visualization. Nucl Acids Res (1 July 2015) 43 (W1): W576-W579 first published online April 29, 2015. doi:10.1093/nar/gkv402) Pictures: Fotolia/adimas and Fotolia/yodiyim

Our aim is to understand and predict the uptake, distribution, transformation and excretion of organic chemicals in organisms. As a predictive tool we are developing a complex mathematical model that simulates all these processes for vertebrates based on a very detailed physiological representation of the organism and based on state-or-the-art understanding of the relevant physico-chemical processes.
This knowledge will help to elucidate bioaccumulation and toxic effects of chemicals and thus improve the risk assessment for chemicals.
In order to construct our mathematical model and to go beyond current state-of-the-art in this so called Physiology-Based-Toxico-Kinetic (PBTK) modelling have been and are still working on various building blocks that we consider as crucial:

Equilibrium partitioning:

Based on our background we have first tackled the questions of equilibrium sorption of organic chemicals to various tissues and organs. In contrast to the often used Kow approach we consider storage lipids and membrane lipids as separate tissues with different sorption properties and we also take into account various proteins such as albumin, muscle proteins and collagen. All these equilibrium partition coefficients are estimated for neutral organic chemicals with our pp-LFER approach (Endo et al, 2013). In contrast, to neutral organic chemicals, sorption processes of ionic species are still not well understood. For sorption of ionic organic species in membrane lipids we have recently presented a promising approach (Bittermann et al., 2014). Sorption of ionic species in storage lipids is assumed to be negligible. In contrast, equilibrium sorption of ionic species to albumin and muscle protein cannot be ignored and is a matter of ongoing research in our group.

Transport across membranes:

In spite of many years of intensive pharmaceutical research there appears to be no sound mechanistic understanding of the passive diffusion of neutral chemicals through lipid bilayers. In a PostDoc project we try to understand this process better and we also follow up on our hypothesis that there may be significant membrane permeability for some ionic species in contrast to the prevalent believe that only neutral species can passively diffuse through membranes. Parallel, we have also done some work on the mathematics of active transport which allows us to easily implement this process into our mathematical model, provided that a parametrization is available.

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