TY - JOUR T1 - Modest Blood-brain Barrier Permeability of the Cyclodextrin Kleptose®: Modification by Efflux and Luminal Surface Binding JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.119.260497 SP - jpet.119.260497 AU - William A. Banks AU - Kory Engelke AU - Kim Hansen AU - Kristin Bullock AU - Perry Calias Y1 - 2019/01/01 UR - http://jpet.aspetjournals.org/content/early/2019/07/18/jpet.119.260497.abstract N2 - Cyclodextrins (CD) 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 (API), most recently for the treatment of Niemann-Pick disease, a lysosomal storage disease. Cyclodextrins are helpful in animal models of and human subjects/patients afflicted with Neimann-Pick disease, including improving the neurological component of the disease. The improvement in brain disease by intravenous administration implies that cyclodextrins can cross the BBB, but there are only a few studies that have directly addressed this. In the current studies, multiple-time regression analysis indicated that the 2-hydroxypropyl-β-cyclodextrin (kleptose ®; Klep) radioactively labeled with 14C (C-Klep) crossed the BBB at a slow rate by a non-saturable mechanism consistent with transcellular diffusion. However, the rate of transport varied greatly by brain region with no detectable uptake by spinal cord; additionally, many regions rapidly reached equilibrium between 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, consistent with renal clearance. In conclusion, we demonstrated minimal uptake of the β-cyclodextrin kleptose by 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 brain to a therapeutic level will likely be difficult to achieve without giving high peripheral doses, bypassing the BBB, or otherwise altering brain penetration. ER -