Model for transport in the central nervous system.

A pharmacokinetic model relating the flux of substances between blood, the compartment consisting of the cerebrospinal fluid (CSF)-extracellular space (ECS) of brain, and brain was developed. Transport equations for diffusion, active transport, and bulk flow of CSF between these three compartments were postulated, and kinetic constants were experimentally obtained. The appropriate differential equations were solved on a digital computer to predict concentrations in CSF and brain as a function of the plasma concentration. The ability of the model to predict correctly CSF and brain concentrations of ascorbic acid and mannitol with only knowledge of the plasma concentrations in both steady-state and nonsteady-state conditions was experimentally tested in rabbits. Ascorbic acid was chosen as a model substance that is actively transported into the CSF-ECS of brain and also into brain cells whereas mannitol enters CSF and brain by diffusion. The model made accurate predictions when the assumptions were not violated. Second, the model showed that the experimentally determined Michaelis-Menten transport constant (KT = 0.8 mg=dl-1) for ascorbate transport from blood into the CSF-ECS of brain optimizes ascorbate homeostasis in brain.