A model was developed to interpret the binding of drugs and physiological substances to plasma proteins to determine how this binding effects the brain uptake of highly bound substances. The model was applied to bilirubin to assess kernicterus in infants. The blood brain barrier 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. Pharmacokinetic analysis of human interferon-alpha was undertaken in plasma and 7 tissues following intravenous bolus and infusion schedules in rats. The results can be applied to optimize the use of this agent in humans. The brain uptake and pharmacokinetics of the therapeutic alkylating drugs melphalan and chlorambucil were measured in rats. Brain concentrations of both were minimal and neither is recommended as first-line treatment for intracerebral tumors in humans. A two dimensional model of vasogenic brain edema was constructed for simulation and prediction of edema in humans as a consequence of disease processes.
