Drug Delivery to the Brain: Physiological Concepts, Methodologies, and Approaches

Abstract

An important property in any central nervous system (CNS) drug is the ability to cross into the brain and reach therapeutic concentrations at safe and acceptable systemic doses. Multiple parameters influence drug availability to the brain. One of the most important of these is the blood-brain barrier (BBB). The vasculature of the brain differs from that of other organs of the body in that it greatly restricts the exchange of most solutes into the brain from the systemic circulation. Equilibration, which only requires seconds to minutes for low molecular weight drugs in the interstitial fluid of most tissues of the body, can require days to weeks for many agents in the brain. The restricted neurovascular exchange is based upon the unique properties of the endothelial cell membranes lining the brain blood vessels which limit the passive diffusion of many polar solutes into the brain and avidly pump out a broad array of polar and nonpolar agents through a series of active efflux transporters.

This chapter presents a conceptual overview of the primary methods to assess brain drug distribution in vivo, providing an insider’s guide to many of the critical steps to use the methods appropriately. Then, two case examples are provided in detail illustrating application and interpretation of specific methods. The entire chapter is written with a perspective of providing an “insider’s view” of the level of drug necessary to reach therapeutic action in the brain. Several parameters are broadly used to explain CNS drug passage and equilibration. One of these is the cerebrovascular permeability-surface area product (PS), which reflects how rapidly a solute can cross in or out of the brain. Another is the brain distribution volume or partition coefficient (K_p,brain), which characterizes the extent (either high or low) that a drug equilibrates in the brain. Because most drugs bind or associate reversibly to proteins, lipids, and other biologic macromolecules, a third parameter is the fraction to which a solute travels freely in the tissue or blood (f_u, the free or unbound fraction). This parameter can be used to calculate the free and bound drug concentrations from the total concentration that is measured by many analytical methods. Together with the time course of drug in the circulation, the above parameters can be used to predict drug total, free, and bound concentrations in brain tissue at all time points after administration. This information can then be used to calculate biologic activity if the binding constant (K_D) of the receptor or the inhibitory constant (K_i) of the signaling process is known. Specific methods, such as in situ brain perfusion, brain efflux index, and in situ brain microdialysis, are valuable to dissect the specific mechanisms operational at the barrier that mediate or regulate drug transport across the brain endothelial cell membranes. In the end, the investigator has a broad array of approaches to assess drug availability to the brain and to make recommendations that would improve outcomes. In some cases, such as for drugs that act in other tissues, the desire may be to limit brain exposure to avoid adverse drug reactions. A specific focus of the chapter is to promote accurate measurements and avoid nonspecific approaches that are error bound and have led to a lot of confusion in the field.