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The role of drug transporters at the blood brain barrier

29 February 2016  •  Author(s): Jasminder Sahi and Yi Li, Sanofi R&D

The human brain is the most highly perfused organ in the body, being composed of over 100 billion capillaries with an average inter-capillary distance of 50μm and a length greater than 600km. This extensive network of blood vessels facilitates the delivery of nutrients and oxygen to the brain, while providing a physical, metabolic and immunologic barrier, the blood brain barrier (BBB), to protect it. The BBB comprises a very tight layer of capillary endothelial cells with elaborate tight junctions between adjacent cells that prevent most soluble materials from crossing, while allowing gases such as oxygen and carbon dioxide to diffuse through.

The role of drug transporters at the blood brain barrier

Passage into the brain from the circulatory system is limited by a number of mechanisms. Endothelial cells of the central nervous system (CNS) have extremely low rates of transcytosis, thereby limiting passage of endogenous substrates and larger molecules. When small molecules diffuse through the cell membrane, the highly expressed efflux transport proteins pump these out, further limiting access to the brain. This efficient and essential barrier is a major hurdle for researchers developing drugs for CNS disorders, since overcoming these protective mechanisms, while reaching the target at an efficacious and safe concentration, is a challenge. Developing drugs becomes increasingly complicated in disease states caused by Alzheimer’s and multiple sclerosis, since the barrier function changes, potentially resulting in alterations in CNS drug exposure.

Membrane transport proteins at the BBB are binned into two categories – uptake and efflux transporters. At the BBB, multiple uptake transporters are responsible for bringing solutes from circulation into the endothelial cells (apical/luminal membrane) and then into the brain across the basolateral membrane. Meanwhile, the efflux transporters pump compounds back into the blood as they traverse the apical cell membrane (i.e., the blood side) and also pump compounds out of the cell into the brain on the basolateral side. These transporters are present at very high concentrations on the apical membrane, and have been studied extensively.

Efflux transporters Multiple efflux transporters are involved in drug transport at the BBB. These include P-glycoprotein (P-gp), breast cancer resistant protein (BCRP) and the multidrug resistance-associated proteins MRP1, MRP3, MRP4 and MRP6. The activities of the efflux transporters at the luminal BBB are dominated by P-gp, followed by BCRP and finally the MRP transporters. P-gp and BCRP work in cooperation as ‘gatekeepers’ of the BBB. The consequence of this cooperation was first demonstrated with the chemotherapeutic agent topotecan, a topoisomerase inhibitor that is transported by both P-gp and BCRP. In a study using transgenic mice, it was shown that brain uptake did not increase much in mice that were deficient in Bcrp (Bcrp1−/−) or P-gp (Mdr1a/1b−/−) and increased dramatically when both transporters were knocked out (Mdr1a/1b−/−Bcrp1−/−). 

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