The need for mathematical modelling of spatial drug distribution within the brain
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(2019) 16:12 Vendel et al. Fluids Barriers CNS https://doi.org/10.1186/s12987-019-0133-x
Open Access
REVIEW
The need for mathematical modelling of spatial drug distribution within the brain Esmée Vendel1, Vivi Rottschäfer1 and Elizabeth C. M. de Lange2*
Abstract The blood brain barrier (BBB) is the main barrier that separates the blood from the brain. Because of the BBB, the drug concentration-time profile in the brain may be substantially different from that in the blood. Within the brain, the drug is subject to distributional and elimination processes: diffusion, bulk flow of the brain extracellular fluid (ECF), extra-intracellular exchange, bulk flow of the cerebrospinal fluid (CSF), binding and metabolism. Drug effects are driven by the concentration of a drug at the site of its target and by drug-target interactions. Therefore, a quantitative understanding is needed of the distribution of a drug within the brain in order to predict its effect. Mathematical models can help in the understanding of drug distribution within the brain. The aim of this review is to provide a comprehensive overview of system-specific and drug-specific properties that affect the local distribution of drugs in the brain and of currently existing mathematical models that describe local drug distribution within the brain. Furthermore, we provide an overview on which processes have been addressed in these models and which have not. Altogether, we conclude that there is a need for a more comprehensive and integrated model that fills the current gaps in predicting the local drug distribution within the brain. Keywords: Mathematical modeling, Drug transport, Brain extracellular fluid, Blood–brain barrier, Pharmacokinetics Introduction The blood–brain barrier (BBB) separates the blood from the brain. The BBB is formed by the brain capillary endothelial cells that constitute the walls of the brain capillaries. Multiprotein complexes called tight junctions are located between adjacent brain capillary endothelial cells and seal the intercellular space, thereby limiting intercellular diffusion. In addition, transport across the BBB is affected by transporters and helper molecules located at the brain capillary endothelial cells that move compounds from the blood to the brain or from the brain to the blood. Consequently, the drug concentration-time profile in the brain may be substantially different from that in the blood [1]. Once in the brain, the drug is subject to distribution and elimination processes: diffusion, bulk flow of the brain extracellular fluid (ECF), extra-intracellular exchange, bulk flow
*Correspondence: [email protected] 2 Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333CC Leiden, The Netherlands Full list of author information is available at the end of the article
of the cerebrospinal fluid (CSF) and metabolism. Furthermore, the drug may bind to specific binding sites (targets) and non-specific binding sites (brain tissue components). Consequently, the drug concentrationtime profile in the b
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