Blood-brain barrier hydrophobic substances

An ability to penetrate lipid bilayers is a prerequisite for the absorption of drugs, their entry into cells or cellular organelles, and passage across the blood-brain barrier. Due to their amphiphilic nature, phospholipids form bilayers possessing a hydrophilic surface and a hydrophobic interior (p. 20). Substances may traverse this membrane in three different ways. 

The particular way in which the walls of the blood vessels in the central nervous system are constructed results in their being impermeable to many substances, thereby limiting the ability of molecules to pass from the blood into the brain. This phenomenon is called the blood-brain barrier. Molecules may cross the blood-brain barrier by mechanisms of active transport, or by being sufficiently lipid soluble that they can diffuse through the hydrophobic core of the lipid membranes that form the boundaries of the cells composing the blood-brain barrier. Most psychoactive drugs are sufficiently lipid soluble that they can pass from the blood into the brain by passive diffusion. 

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. 

The cells of the blood brain barrier (BBB) are closely linked by tight junctions, which practically prevent hydrophilic molecules to diffuse between the cells into the central nervous system (CNS). However, as hydrophobic substances might diffuse through the membrane, it is the role of P-gp to keep those out as well (Neuhaus Noe, 2009). The protecting function of P-gp at the BBB has been observed with mdrl knock-out mice and the dog breed collie, which naturally lacks functional P-gp because of a mutated mdrl gene. Collies are extremely susceptible to neurotoxic drugs and thus show dramatic adverse reactions after treatment with the antiparasitic drug ivermectin (Mealey et al., 2001). 

---