Melphalan, an anticancer alkylating agent, was measured in the blood and brain of rats and its pharmacokinetics determined. It enters the brain via an amino acid transport system at the blood-brain barrier; its entry is related to its plasma protein binding, which is concentration-dependent. The blood-brain barrier was not affected by dimethyl sulfoxide, but could be opened in rats and mice by intracarotid infusion of a hypertonic arabinose solution. The rate of reclosure was related to the size of the intravascular tracer, indicating that tight junctions between cerebrovascular endothelial cells were modified. Reversible osmotic barrier opening was used to deliver interferon to the brain of rats. A mathematical model for uptake and metabolism of glucose by brain was developed and used to interpret glucose transport during hypoglycemia and hyperglycemia. Brain uptake of the food dye erythrosin B is restricted by its binding to plasma protein, and not by its impermeability at the blood-brain barrier. Bilirubin was allowed into the brain of rats following osmotic opening of the blood-brain barrier, and shown to have a cerebral half-time of 1.7 hours. Retained bilirubin in human kernicterus therefore probably reflects neonatal brain damage.
