Fig. 1  Permeation mechanisms across the BBB: (1) paracellular diffusion between the cells of the capillary endothelium. (2) Transcellular diffusion; solutes with sufficient lipid solubility may passively diffuse through the cell membranes of the endothelial cells and enter the brain. (3) Carrier-mediated transport of more hydrophilic molecules is via SLCs inserted into the luminal and/or abluminal membrane. These may be (a) facilitated bi-directional carriers operating in the direction of the concentration gradient, (b/c) uni-directional into or out of the cell (d) co-transporters/exchangers co-transporting or exchanging another solute or ion in the same or opposite direction. (4) Active efflux carriers (ABC transporters) may pump out a wide range of passively penetrating solutes either from the cytoplasmic compartment or directly from the cell membrane. (5) Transcytosis can also occur which may be non-specific (fluid phase, very limited at the BBB) or specific. Specific mechanisms include absorptive-mediated transcytosis (AMT), which involves an electrostatic interaction between a positively charged substance and the negatively charge plasma membrane surface, or receptor-mediated transcytosis (RMT), which involves a receptor (Rc) and is highly selective for specific molecules.