Biomedical Engineering Reference
In-Depth Information
14.1. INTRODUCTION
Pharmacotherapy of central nervous system (CNS) diseases remains difficult, due
to limited drug permeation across the blood-brain barrier and blood-cerebrospinal
fluid barrier. Therapeutic compounds may cross these barriers by several uptake
processes, including transcytosis, receptor-mediated endocytosis, passive diffusion,
carrier-mediated (facilitated) transport, and/or active transport.
1
Once across these
initial barriers, brain drug accumulation can be restricted further by passive efflux
within the cerebrospinal fluid (sink effect), metabolic degradation, and/or active ef-
flux transport. In addition, brain parenchymal cellular compartments (i.e., astrocytes,
microglia, oligodendrocytes, and neurons) also play an important role in regulating
CNS drug distribution. These cells express several drug transport proteins, which
underscore the complexity of xenobiotic disposition within the brain. The objective
of this chapter is to summarize the current knowledge on the molecular expression
(i.e., gene, protein), cellular localization, and functional activity of drug transporters
in the brain.
14.2. PHYSIOLOGY OF THE BRAIN BARRIERS AND BRAIN
PARENCHYMA
14.2.1. Blood-Brain Barrier
The blood-brain barrier (BBB) constitutes a remarkable physical and biochemical
barrier between the brain and systemic circulation.
2
Structurally, the BBB is com-
posed of a monolayer of nonfenestrated microvessel endothelial cells surrounded by
pericytes and perivascular astrocytes. Brain microvessel endothelial cells are joined
by tight junctions (i.e., zonulae occludens), which are maintained by trophic factors
released from adjacent astrocytes.
3
,
4
Under physiological conditions, these tight junc-
tions form a continuous, almost impermeable cellular barrier that limits paracellular
flux and transport as well as the influx of endogenous and exogenous substances,
with the exception of very small lipid-soluble molecules.
5
The high transendothelial
electrical resistance (1500 to 2000
ยท
cm
2
) of the BBB further restricts the free flow
of water and solutes.
6
Several receptors, ion channels, and influx-efflux transport proteins are ex-
pressed prominently at the BBB. Functionally, brain transporters are similar to well-
characterized systems in other tissues (e.g., D-glucose transporter, L-amino acid car-
rier systems, Na
+
/K
+
-ATPase), although the capacity and rate of transport can vary
widely.
7
At the level of brain microvascular endothelium, many of these membrane-
bound transport systems are distributed asymmetrically. One example of this asym-
metry involves the facilitative glucose transporter, GLUT-1, which is expressed to a
fourfold greater degree at the abluminal side of the BBB than at the luminal side.
8
In addition to these transport systems, endocytosis of macromolecules has also
been reported at the BBB.
9
Receptor-mediated and adsorptive endocytotic processes
in brain endothelium have been documented for both hormones and plasma proteins.
10
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