Confounding Parameters in Preclinical Assessment of Blood–Brain Barrier Permeation: An Overview With Emphasis on Species Differences and Effect of Disease States

Drug delivery across the brain–blood interfaces is a complex process involving physicochemical drug properties, transporters, enzymes, and barrier dysfunction in diseased conditions. Intact blood–brain barrier (BBB) limits the entry of potentially harmful compounds into the brain but may also reduce the CNS permeability of therapeutic agents. BBB permeability is typically assessed by measuring brain-to-plasma ratio in rodents (referred to as B/P ratio, BB, or Kp, often calculated as logBB), an approach that suffers significant limitations as discussed in the present review. Kp is not a permeability measurement but a partition coefficient mainly driven by the relative binding to plasma and brain tissue components including lipids, phospholipids, and proteins. Compounds with high Kp are often lipophilic with low free fraction available to mediate CNS activities. Efforts should be more concentrated on measuring pharmacologically relevant free drug concentrations at the target site. Using healthy rodents to p...