18 Figure 1. The blood-brain barrier and drug transporters in the capillary endothelial cells. The choroid plexus is a highly vascularized epithelial organ which secretes the cerebrospinal fluid and regulates its composition through active and selective transport processes; it has an active role in the cleansing of the cerebrospinal fluid of endogenous and exogenous compounds.19 The blood cerebrospinal barrier (CSB) is considered as the second Inhibitors,research,lifescience,medical fluid barrier protecting the central nervous system: it is principally formed by epithelial cells of the choroid plexus in the ventricles and the

arachnoid membrane. Like the brain capillary endothelial cells, the choroid plexus epithelial cells are connected by high-resistance Inhibitors,research,lifescience,medical tight junctions, which closely separate the blood from the cerebrospinal fluid compartment (Figure 2).20 Figure 2. The cerebrospinal barrier and drug transporters in the choroid plexus cells. Together with the BBB and the CSB, the membrane transporter systems represent further gatekeepers to the CNS; these play a critical role in drug disposition.21 Membrane transporters either enhance or restrict drug Azacitidine concentration distribution to the target Inhibitors,research,lifescience,medical organs. Depending on their main function, these

membrane transporters are divided into two categories: the efflux (export) and the influx (uptake) transporters. Influx transport proteins facilitate and efflux transporters limit drug passage through membrane barriers such as the BBB or the CSB.22 Several membrane transporters are found at the apical and basolateral epithelial cell membrane of the brain capillary and of the choroid plexus endothelial cells

(Figure 3).23 Figure 3. Examples of drug transporters and localization in cells forming the CNS barriers. CNS, central nervous Inhibitors,research,lifescience,medical system; SLC, solute-linked carrier. Pharmacological aspects Drug absorption from the systemic circulation into the CNS was previously considered a passive process that depended on drug physicochemical properties such as molecular size, lipophilicity, and the pKa of a drug. Although the physicochemical Inhibitors,research,lifescience,medical properties of secondly a medication do affect its absorption and access to target organs, transporter proteins have a major role in the overall drug distribution process through their targeted expression in tissue such as the brain. Until recently, most pharmacokinetic studies focused only on the role of drugmetabolizing enzymes as a key determinants of drug disposition.24 Phase I enzymatic reactions are mainly represented by the cytochrome P450 mono-oxygenase system, as well as by other enzymes such as pseudocholinesterase or alcohol dehydrogenase. Phase I enzymatic reactions modify the chemical structure of the compound itself with either loss of pharmacological activity or, on the contrary, when prodrugs are administered, enhanced biological activity through biotransformation into an active metabolite.