Blood-brain barrier drug efflux system

Role of Drug Efflux Transport Systems in the Blood-Brain Barrier..604... 

Kusuhara H, Sugiyama Y. 2001. Efflux transport systems for drugs at the blood-brain barrier and blood-cerebrospinal fluid barrier. Part 1. Drug Discov. Today 6(3) 150-56... 

Figure 3.2. Potential mechanisms for drug movement across the blood-brain barrier. Routes of passage include passive diffusion through the brain capillary endothelial cells (A) utilization of inwardly directed (i.e. towards brain) transport or carrier systems expressed on brain capillary endothelial cells (B) utilization of outwardly directed (i.e. towards blood) efflux transport systems (C) or inclusion in various endocytic vesicular transport processes occurring within the brain capillary endothelial cells (D).

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. 

Drug distribution in such sites or compartments is a complex process that depends on the systemic circulation concentration and subsequent passage across single cell endothelial or epithelial membranes with specialized physical and molecular barrier functionality. For certain orally administered AIDS medications (e.g., zidovudine and didanosine), oral absorption is limited because of poor absorption from the G1 tract, enzymatic biotransformation in the intestinal epithelium, or first-pass effects (Sinko et al., 1995, 1997). For other AIDS drugs (e.g., protease inhibitors), oral absorption may be complete however, drug distribution into the brain is limited by drug efflux proteins, which promiscuously interact and translocate lipophilic substrates back into blood as they diffuse into the BBB endothelium (Edwards et al., 2005 Kim et al., 1998). 

---