AbstractThe development of drugs targeting the brain still faces a high failure rate. One of the reasons is a lack of quantitative understanding of the complex processes that govern the pharmacokinetics (PK) of a drug within the brain. While a number of models on drug distribution into and within the brain is available, none of these addresses the combination of factors that affect local drug concentrations in brain extracellular fluid (brain ECF).Here, we develop a 3D brain unit model, which builds on our previous proof-of-concept 2D brain unit model, to understand the factors that govern local unbound and bound drug PK within the brain. The 3D brain unit is a cube, in which the brain capillaries surround the brain ECF. Drug concentration-time profiles are described in both a blood-plasma-domain and a brain-ECF-domain by a set of differential equations. The model includes descriptions of blood plasma PK, transport through the blood-brain barrier (BBB), by passive transport via paracellular and trancellular routes, and by active transport, and drug binding kinetics. The impact of all these factors on ultimate local brain ECF unbound and bound drug concentrations is assessed.In this article we show that all the above mentioned factors affect brain ECF PK in an interdependent manner. This indicates that for a quantitative understanding of local drug concentrations within the brain ECF, interdependencies of all transport and binding processes should be understood. To that end, the 3D brain unit model is an excellent tool, and can be used to build a larger network of 3D brain units, in which the properties for each unit can be defined independently to reflect local differences in characteristics of the brain.Author summaryInsights on how a drug distributes within the brain over both time and space are still limited. Here, we develop a ‘3D brain unit model’ in order to understand the factors that control drug concentrations within a small piece of brain tissue, the 3D brain unit. In one 3D brain unit, the brain capillaries, which are the smallest blood vessels of the brain, surround the brain extracellular fluid (ECF). The blood-brain barrier (BBB) is located between the brain capillaries and the brain ECF. The model describes the impact of brain capillary blood flow, transport across the BBB, diffusion, flow and drug binding on the distribution of a drug within the brain ECF. We distinguish between free (unbound) drug and drug that is bound to binding sites within the brain. We show that all of the above mentioned factors affect drug concentrations within brain ECF in an interdependent manner. The 3D brain unit model that we have developed is an excellent tool to increase our understanding of how local drug concentrations within the brain ECF are affected by brain transport and binding processes.
Modeling the Effect of Binding Kinetics in Spatial Drug Distribution in the Brain