The 3D Brain Unit Network Model to Study Spatial Brain Drug Exposure under Healthy and Pathological Conditions
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RESEARCH PAPER
The 3D Brain Unit Network Model to Study Spatial Brain Drug Exposure under Healthy and Pathological Conditions Esmée Vendel 1 & Vivi Rottschäfer 1 & Elizabeth C.M. de Lange 2
Received: 26 September 2019 / Accepted: 9 January 2020 / Published online: 9 July 2020 # The Author(s) 2020
ABSTRACT Purpose We have developed a 3D brain unit network model to understand the spatial-temporal distribution of a drug within the brain under different (normal and disease) conditions. Our main aim is to study the impact of disease-induced changes in drug transport processes on spatial drug distribution within the brain extracellular fluid (ECF). Methods The 3D brain unit network consists of multiple connected single 3D brain units in which the brain capillaries surround the brain ECF. The model includes the distribution of unbound drug within blood plasma, coupled with the distribution of drug within brain ECF and incorporates brain capillaryblood flow, passive paracellular and transcellular BBB transport, active BBB transport, brain ECF diffusion, brain ECF bulk flow, and specific and nonspecific brain tissue binding. All of these processes may change under disease conditions. Results We show that the simulated disease-induced changes in brain tissue characteristics significantly affect drug concentrations within the brain ECF. Conclusions We demonstrate that the 3D brain unit network model is an excellent tool to gain understanding in the Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11095-020-2760-y) contains supplementary material, which is available to authorized users. * Vivi Rottschäfer [email protected] * Elizabeth C.M. de Lange [email protected] Esmée Vendel [email protected] 1
Mathematical Institute, Niels Bohrweg 1, 2333CA, Leiden, The Netherlands
2
Leiden Academic Center for Drug Research, Einsteinweg 55, 2333CC, Leiden, The Netherlands
interdependencies of the factors governing spatial-temporal drug concentrations within the brain ECF. Additionally, the model helps in predicting the spatial-temporal brain ECF concentrations of existing drugs, under both normal and disease conditions.
KEY WORDS Brain extracellular fluid . pharmacokinetics . mathematical . model . drug binding . drug transport
ABBREVIATIONS BBB brain ECF PK
blood-brain barrier brain extracellular fluid pharmacokinetics
INTRODUCTION Insight into the spatial-temporal distribution of a drug within the brain is still limited, but very important for improved understanding of drug interaction with binding sites and ultimately drug effects and side effects. The blood-brain barrier (BBB) is a major barrier of the brain and separates the blood plasma in the brain capillaries from the brain extracellular fluid (brain ECF). The BBB has great impact on the relationship between drug concentration-time profiles (pharmacokinetics; PK) within the blood plasma and the brain ECF (see i.e. (1)). However, there is a lack of understanding of the mechanisms that may lead to
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