Efflux Mechanisms in the Central Nervous System: A Powerful Influence on Drug Distribution within the Brain

TY - CHAP

T1 - Efflux Mechanisms in the Central Nervous System

T2 - A Powerful Influence on Drug Distribution within the Brain

AU - Begley, David J.

PY - 2003/11/21

Y1 - 2003/11/21

N2 - The blood-brain and blood-cerebrospinal fluid (CSF) barriers are able to form an effective barrier to most polar solutes as the expression of tight junctional protein complexes between the endothelial cells of the cerebral vasculature effectively abolish any aqueous paracellular diffusional pathway between blood and brain. However, a large number of more lipophilic solutes are still potentially able to cross the barriers by passive means. In general the more lipid soluble a molecule is, the greater is its potential for passively partitioning into brain tissue. A large number of both endogenous and xenobiotic substances however, partition into brain to an extent that is far less than might be predicted by their lipid solubility. It has recently become apparent that a multitude of molecules that are potentially able to passively enter the brain are effluxed by specific transporters located at the blood-brain interfaces. These transporters actively extrude many compounds from the CNS thus limiting their brain-uptake. A primary function of the blood-brain and blood-csf barriers is to preserve homeostasis within the cerebral compartment so that the complex neural integrative functions of the CNS can operate optimally. A further crucial function of the barriers is that of neuroprotection. Many of the substrates of the CNS efflux transporters are actually neurotoxic or may possess CNS pharmacological activity. In a complex tissue such as the CNS, where cell division is either slow, or absent in the case of neurones, an acceleration in cell death will become prematurely debilitating. Thus, the physiological role of CNS efflux transporters is to regulate and to significantly reduce the CNS entry of many potentially neurotoxic and neuroactive substances. As many prescribed drugs designed for CNS targets are also substrates for the transporters their presence in the blood-brain interfaces presents a major challenge to the pharmaceutical industry.

AB - The blood-brain and blood-cerebrospinal fluid (CSF) barriers are able to form an effective barrier to most polar solutes as the expression of tight junctional protein complexes between the endothelial cells of the cerebral vasculature effectively abolish any aqueous paracellular diffusional pathway between blood and brain. However, a large number of more lipophilic solutes are still potentially able to cross the barriers by passive means. In general the more lipid soluble a molecule is, the greater is its potential for passively partitioning into brain tissue. A large number of both endogenous and xenobiotic substances however, partition into brain to an extent that is far less than might be predicted by their lipid solubility. It has recently become apparent that a multitude of molecules that are potentially able to passively enter the brain are effluxed by specific transporters located at the blood-brain interfaces. These transporters actively extrude many compounds from the CNS thus limiting their brain-uptake. A primary function of the blood-brain and blood-csf barriers is to preserve homeostasis within the cerebral compartment so that the complex neural integrative functions of the CNS can operate optimally. A further crucial function of the barriers is that of neuroprotection. Many of the substrates of the CNS efflux transporters are actually neurotoxic or may possess CNS pharmacological activity. In a complex tissue such as the CNS, where cell division is either slow, or absent in the case of neurones, an acceleration in cell death will become prematurely debilitating. Thus, the physiological role of CNS efflux transporters is to regulate and to significantly reduce the CNS entry of many potentially neurotoxic and neuroactive substances. As many prescribed drugs designed for CNS targets are also substrates for the transporters their presence in the blood-brain interfaces presents a major challenge to the pharmaceutical industry.

UR - http://www.scopus.com/inward/record.url?scp=84942939970&partnerID=8YFLogxK

U2 - 10.1016/B978-012639011-7/50013-9

DO - 10.1016/B978-012639011-7/50013-9

M3 - Chapter

SN - 9780126390117

SP - 83

EP - 97

BT - Blood-Spinal Cord and Brain Barriers in Health and Disease

PB - Elsevier Inc.

ER -