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: Blood–brain barrier; Brain extracellular fluid; Drug transport; Mathematical modeling; Pharmacokinetics.