Distribution: Across Barriers

Distribution of drugs across barriers plays a predominant role in the processes of absorption (A), distribution (D), and excretion (E) and is thus a major determinant of a drugs pharmacokinetic profile. The barrier at the site of absorption is in most cases built by the enterocytes of the small intestine (see chapter “Absorption: In Vivo Tests (Radiolabeled)”). Apart from lung, heart, muscle, and brain, the main target organs are kidney and liver which are also the major elimination pathways of drugs. Cell membranes of liver hepatocytes and kidney cells have to be passed in these cases. The brain plays a special role in the distribution of drugs because drugs normally should not enter the central nervous system to avoid severe adverse effects. It is, therefore, protected by the very tight blood–brain barrier. However, when the target is located in the brain, the drug needs to cross this barrier. Meanwhile, there exist several in vitro systems to study drug permeation across this special blood–brain barrier (section “Blood–Brain Barrier (BBB)”). They cover primary cultures of brain endothelial cells in monoculture or as coculture with astrocytes or pericytes (section “Primary Cultures of Brain Capillary Endothelial Cells”), immortalized endothelial cell lines from different species (section “Cocultures of Bovine Brain Microvascular Endothelial Cells and Rat Astrocytes”), and surrogate models (section “A Surrogate BBB Model: MDCK-MDR1 Cells”).