After osmotic opening, the blood-brain barrier (BBB) has been shown to reclose more rapidly to large than to small neutral, water-soluble molecules. Quantitative analysis of these data supports the creation of interendothelial pores with radii of about 200 A through which such molecules pass by both restricted diffusion and bulk flow (with solute drag) from blood to brain. 2. The major reduction in BBB permeability from 6 to 35 min following osmotic opening seems to be due to a reduction in bulk flow by a factor of about 10, rather than marked decreases in pore densities or effective pore size. On this basis, quantitative predictions of brain uptake of neutral, water soluble substances are made for various times after osmotic opening of the BBB, as a function of molecular size. 3. Implications of these results are discussed for enhancement of uptake of drugs, including enzymes and certain anti-cancer agents, by the brain. 4. The idea of a 'therapeutic window' as the period of time, following reversible osmotic opening, during which the permeability of the BBB is enhanced significantly for a particular compound, is introduced. Since the BBB is normally highly impermeable to plasma proteins, the effect of BBB opening on the uptake of highly protein-bound drugs is discussed briefly. 5. The effect of molecular charge on the passage of molecules through interendothelial pores into the brain is also discussed.
