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Cyclodextrins (CDs) have a variety of uses from acting as excipients to aiding the ability of lipid soluble drugs to cross the blood-brain barrier (BBB). They are being investigated as an active pharmaceutical ingredient, most recently for the treatment of Niemann-Pick disease, a lysosomal storage disease. Cyclodextrins are helpful in animal models and human subjects/patients afflicted with Neimann-Pick disease, including improving the neurologic component of the disease. The improvement in brain disease by intravenous administration implies that CDs can cross the BBB; however, there are only a few studies that have directly addressed this. In the current studies, multiple-time regression analysis indicated that 2-hydroxypropyl- β -cyclodextrin [Kleptose (Klep)] radioactively labeled with 14C (C-Klep) crossed the BBB at a slow rate by a nonsaturable mechanism consistent with transcellular diffusion. However, the rate of transport varied greatly by the brain region with no detectable uptake by the spinal cord; additionally, many regions rapidly reached equilibrium between the brain and blood. The presence of a brain-to-blood efflux system was also detected and much of the C-Klep did not completely cross the BBB, but loosely adhered to the luminal surface of brain endothelial cells. Peripheral tissues also took up C-Klep, with the kidney taking up the most, which is consistent with renal clearance. In conclusion, we demonstrated minimal uptake of the β -cyclodextrin Kleptose by the brain with accumulation being affected by efflux and reversible luminal binding. SIGNIFICANCE STATEMENT: This cyclodextrin, which produces therapeutic effects on the central nervous system after peripheral administration, penetrates the BBB poorly. Uptake by the brain to a therapeutic level will likely be difficult to achieve without giving high peripheral doses, bypassing the BBB, or otherwise altering penetration into the brain.

Modest Blood-Brain Barrier Permeability of the Cyclodextrin Kleptose: Modification by Efflux and Luminal Surface Binding