The substrates handled by the ABC transporters include a wide range of endogenous and exogenous compounds and diverse type of molecules, from organic cations and anions to larger molecules such as large polypeptides or therapeutic agents. For instance, MRP1 has preferential transport of anionic compounds such as sulfate conjugates or glutathione, whereas MDR1 shows broader substrate specificity.31,32 Variation of ABC transporter

activity by drug-drug interactions, genetic polymorphisms, and overexpression is considered as a major cause of treatment failure, interindividual variability, and adverse drug reactions.25,33 However, randomized controlled studies on these issues with Inhibitors,research,lifescience,medical antidepressants, antipsychotics, or mood stabilizers in humans are still lacking. ABC transporters are considered as the most relevant determinants of efflux transport

and provide multiple barriers in the brain capillary and choroid plexus endothelial cells.34 A multidrug resistance feature is associated with Inhibitors,research,lifescience,medical a poorer Inhibitors,research,lifescience,medical clinical outcome in several CNS disorders.24 Furthermore, several ABC transporters were directly implicated in drug delivery to brain neoplasms and in the response to therapeutic agents.35 For instance, the expression of the ABC transporters ABCC4 and ABCC5 was associated with an astrocytic phenotype with higher chemoresistance of astrocytic tumors compared with oligodendrogliomas.36 Recently, the ABC transporters were also found to be associated with pharmacoresistance to anticonvulsant drugs in patients Inhibitors,research,lifescience,medical with intractable mesial temporal lobe epilepsy37 MDR1 activity significantly decreases during aging with, consecutively, an increased brain exposure to drugs and toxins in elderly subjects.38 Furthermore, impaired MDR1 function is thorough reported as a predisposing factor in the development of neurodegenerative diseases such Inhibitors,research,lifescience,medical as Parkinson’s disease

or sporadic Alzheimer’s dementia.39 Pathologic accumulation of amyloid β in Alzheimer’s disease may result from an impaired MDR1 activity, as amyloid β is considered Cilengitide as a substrate for MDR1.13 SLC transporters The SLC class of solute carriers consists of specific membrane transporters that mediate sodium-independent transmembrane solute transport: it is divided into 43 human families based upon amino acid homology of at least 25% between family members. To date, nearly 300 genes have been identified.40 The Human Genome Organization (HUGO) Nomenclature Committee Database provides information about new transporter families of the SLC gene series (SLC transporters-gene nomenclature, SLCO).41 Members of the SCLO superfamily are not only expressed in the BBB and in the choroid plexus, but also in the small intestine, the liver, the kidney, the blood-testis barrier, and the placenta.