Despite advances in therapies for brain diseases, many patients are resistant to drug treatment. The biological basis of drug resistance is not completely understood, but is likely to include insufficient drug penetration to the brain regions or brain cells involved in the disease, which are the target of drug therapy.Drugs that are used to treat brain diseases must penetrate from the blood to their site of action. Drug uptake into the brain depends on various factors, including the involvement of the physical barriers presented by the blood–brain barrier (BBB) and the blood–cerebrospinal fluid (blood–CSF) barrier, and drug affinity for specific transport systems located at both of these interfaces.Various drugs used in the treatment of brain disorders are substrates for drug efflux transporters in the BBB and blood–CSF barrier. These transporters include the product of the multidrug resistance 1 (MDR1, also known as ABCB1) gene, P-glycoprotein (Pgp), and several members of the multidrug resistance protein (MRP, also known as ABCC) family.Such membrane drug transporters, which actively shuttle drugs across the cell membrane, thereby extruding these drugs from the cell, were first identified in chemotherapy-resistant cancer cells, but were subsequently also found in many healthy body tissues. They protect cells or tissues from the accumulation of lipophilic xenobiotics that would otherwise freely penetrate cell membranes.In the CNS, such drug transport systems influence the brain disposition and efficacy of many pharmacological agents that are used to treat brain cancers, epilepsy, depression, schizophrenia, CNS-based pain, and bacterial or viral infections of the CNS. Multidrug transporters such as Pgp are, therefore, thought to be important in the mechanisms that underlie drug resistance in brain diseases.Multidrug transporters can contribute to drug resistance by their constitutive expression in the BBB and blood–CSF barrier, thereby restricting the brain access of numerous drugs and enhancing drug extrusion from the brain, so that the concentrations of drugs in the brain cannot become sufficiently high for therapeutic efficacy. Furthermore, in some brain diseases, such as brain tumours, HIV and epilepsy, intrinsic or acquired overexpression of multidrug transporters in the BBB or brain target tissue limits drug penetration into that tissue.The expression of drug efflux transporters in the brain is under tight transcriptional regulation by orphan nuclear receptors, such as the pregnane X receptor, but is also affected by environmental stimuli that evoke stress responses and by endogenous neurotransmitters, such as glutamate. Furthermore, polymorphisms in transporter genes can alter the expression and functionality of drug efflux transporters such as Pgp and might be involved in the drug resistance of brain diseases.Modulating or bypassing such transporters at the BBB might be useful future strategies for improving drug therapy. Mechanisms by which efflux transporter activity in the BBB can be modulated include direct inhibition by specific inhibitors, functional modulation, and transcriptional modulation.With respect to the ultimate proof of any resistance-mediating mechanism — showing that modulating the mechanism improves the tractability of the disease — different strategies, including inhibition of Pgp, are currently being evaluated in brain cancer and epilepsy. If these strategies prove successful, they will certainly be applied to other treatment-resistant brain diseases.
