Efflux Transport Barriers in the CNS

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Besides the physiologic barriers discussed above, there are several passive and active efflux mechanisms that will influence drug concentrations in the brain (Fig. 2). Active efflux of drugs from the CNS by these transporters may result in reduced drug concentration, even though drugs possess preferable physicochemical properties for BBB penetration (e.g., lipid solubility). Efflux mechanisms in the CNS include multi-drug resistance protein (MRP), P-gp and breast cancer resistant protein (BCRP), all of which belong to the ATP-binding cassette (ABC) family of transport proteins (15,16). Many lipophilic drugs are substrates for P-gp (Table 1), MRPs or organic anion transporting polypeptides (OATPs) that are expressed in brain capillary endothelial cells and/or astrocytes and are key elements of the molecular machinery that confers special permeability properties to the BBB. The combined action of these carrier systems results in rapid efflux of xenobiotics from the CNS (17).

The MRP family consists of least five isoforms with different levels of expression in different tissues in humans. The MDR gene produces P-gp, which exists in the luminal membranes of the cerebral capillary endothelium and actively effluxes lipid soluble substrates from cells. ABC efflux transporters in the BBB can minimize neurotoxic adverse effects of drugs that otherwise would penetrate into the brain. Modulation of ABC efflux transporters at the BBB forms a novel strategy to enhance the penetration of drugs into the brain and may yield new therapeutic options for drug-resistant CNS disease (18). Therefore, drug delivery to CNS can be increased not only by enhancing influx, but also by inhibiting efflux through the BBB.

Figure 2 Illustration of drug efflux proteins expressed in the BBB. The proposed direction of the transport is indicated by arrows. Efflux transporters that are localized on the luminal side of the brain capillary endothelium function to restrict brain uptake of xenobiotics. Transporters that mediate intracellular uptake at the basolateral membrane may act in concert with efflux transporters at the apical membrane, thereby enhancing extrusion of drugs from the brain. Included in the figure are members from the ABC family of transporters including p-glycoprotein (P-gp), breast cancer resistant protein (BCRP), multidrug resistance proteins (MRPs). The organic anion transporting polypeptides (OATPs) are also depicted. Source: Reprinted from Ref. 17 with permission.

Figure 2 Illustration of drug efflux proteins expressed in the BBB. The proposed direction of the transport is indicated by arrows. Efflux transporters that are localized on the luminal side of the brain capillary endothelium function to restrict brain uptake of xenobiotics. Transporters that mediate intracellular uptake at the basolateral membrane may act in concert with efflux transporters at the apical membrane, thereby enhancing extrusion of drugs from the brain. Included in the figure are members from the ABC family of transporters including p-glycoprotein (P-gp), breast cancer resistant protein (BCRP), multidrug resistance proteins (MRPs). The organic anion transporting polypeptides (OATPs) are also depicted. Source: Reprinted from Ref. 17 with permission.

Inhibition can be achieved by co-administering an inhibitor of the efflux transport protein. Transport inhibition can be utilized as a novel therapeutic approach to modulate or by-pass drug efflux transporters at the BBB to treat drug-resistant brain diseases.

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