Brain Efflux Index Method: Characterization of Efflux Transport Across the Blood-Brain Barrier

Efflux transport systems act as one of the detoxification systems at the blood-brain barrier (BBB) by eliminating xenobiotics and endogenous wastes from the brain into the blood (1 –6 ). P-glycoprotein is a well-known example (1 ,2 ,5 ,6 ). It is a primary active transporter for hydrophobic neutral and cationic compounds and mediates unidirectional transport from the inside to the outside of cells. The distribution of its substrates in the brain after its intravenous administration is significantly increased, by twofold to approx 20-fold, depending on the substrates in P-glycoprotein knockout mouse (1 ,2 ,5 ,6 ). Although the molecular mechanism has not been fully elucidated, the presence of an efflux transport system for organic anions on the brain capillary endothelial cells has been suggested (1 –5 ). It is necessary to reveal the efflux transport mechanisms at the BBB to understand the disposition of nutrients and neurotransmitters and their metabolites in the central nervous system, and to deliver central acting drugs to the central nervous system efficiently. A method to determine in vivo efflux clearance across the BBB is required for that purpose.