Active efflux transporters blood-brain barrier

Kabanov, A. Y., E.V. Batrakova, and D.W. Miller. 2003. Pluronic block copolymers as modulators of drug efflux transporter activity in the blood-brain barrier. Adv Drug Deliv Rev 55 151. 

The study of active transport mechanisms has grown substantially in recent years, with transport proteins such as P-gp, BCRP, and MRP-2 among the most studied [59]. Several types of in vitro assays to assess substrates of transporters have been established these include assays directed toward intestinal and biliary efflux [60]. Assays that measure passive and active transport are also used to assess penetration of the blood-brain barrier. In addition to the assays described above, transfected cell lines that overexpress transporters present in the blood-brain barrier are also employed [61]. 

Active efflux transporters also exist in the placenta, analogous to the gut and blood-brain barrier. These are Pgp, multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP). These transport proteins are located in many tissues but also appear to be expressed in the placenta. Though the substrate specificities of these proteins have not been completely described, they appear to function as efflux transporters, moving endogenous and exogenous chemicals from the placental cells back to the systemic circulation. In this way, they serve as a mechanism to protect the fetus from exposure to unintended chemicals. 

Ehrlich (1) and Goldman (2) were the hrst to observe the existence of the blood-brain barrier (BBB) after the inj ection of the hydrophilic compound trypan blue in a rat did not distribute into and out of the brain. It is now known that the cerebral capillary regulates the influx and efflux of biologically important molecules both by preventing passive hydrophilic diffusion and by providing transport processes whose activity can be regulated in accordance with the metabolic and homeostatic requirements of the brain. 

P-glycoprotein is considered as the most important ABC efflux transporter (ABCBl, MDRl) at the blood-brain barrier [54]. It is a member of the ABC family and consumes ATP during its active efflux transport mechanisms. The major role of P-gp in the phenomenon of multidrug resistance is attributed to its broad substrate specificity. 

Loscher, W. and Potschka, H. (2005) Blood-brain barrier active efflux transporters ATP-binding cassette gene family. NeuroRx, 2, 86-98. 

All these models describe small data sets with only limited predictability for other series of compounds. With the increasing importance of combinatorial chemistry and high-throughput screening, it became necessary to formulate more general models for oral bioavailability and blood-brain barrier permeability. Such quantitative models for oral bioavailability are difficult to derive there is a lack of consistent data and many drugs are either absorbed by an active transport (e.g., by the amino acid or dipeptide transporters), or are eliminated by one of several different efflux pumps. 

The endothelial cells actively, as well as passively, serve to protect the brain. Because they contain a variety of drug-metabolizing enzyme systems similar to the drug-metabolizing enzymes found in the liver, the endothelial cells can metabolize neurotransmitters and toxic chemicals and, therefore, form an enzymatic barrier to entry of these potentially harmful substances into the brain. They actively pump hydrophobic molecules that diffuse into endothelial cells back into the blood (especially xenobiotics) with P-glycoproteins, which act as transmembranous, ATP-dependent efflux pumps. Although lipophilic substances, water, oxygen, and carbon dioxide can readily cross the blood-brain barrier by passive diffusion, other molecules depend on specific transport systems. Differential transporters on the luminal and abluminal endothelial membranes can transport compounds into, as well as out of, the brain. 

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