The role of size and charge for blood-brain barrier permeation of drugs and fatty acids

Seelig, A.. (2007) The role of size and charge for blood-brain barrier permeation of drugs and fatty acids. Journal of Molecular Neuroscience, 33 (1). pp. 32-41.

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Official URL: http://edoc.unibas.ch/dok/A5258456

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The lipid bilayer is the diffusion barrier of biological membranes. Highly protective membranes such as the blood-brain barrier (BBB) are reinforced by ABC transporters such as P-glycoprotein (MDR1, ABCB1) and multidrug resistance associated proteins (MRPs, ABCCs). The transporters bind their substrates in the cytosolic lipid bilayer leaflet before they reach the cytosol and flip them to the outer leaflet. The large majority of drugs targeted to the central nervous system (CNS) are intrinsic substrates of these transporters. Whether an intrinsic substrate can cross the BBB depends on whether passive influx is higher than active efflux. In this paper, we show that passive influx can be estimated quantitatively on the basis of Stokesian diffusion, taking into account the ionization constant and the cross-sectional area of the molecule in its membrane bond conformation, as well as the lateral packing density of the membrane. Active efflux by ABC transporters was measured. The calculated net flux is in excellent agreement with experimental results. The approach is exemplified with several drugs and fatty acid analogs. It shows that compounds with small cross-sectional areas (A(D) > 70 A(2)) and/or intermediate or low charge exhibit higher passive influx than efflux and, therefore, cross the BBB despite being intrinsic substrates. Large (A(D) < 70 A(2)) or highly charged compounds show higher efflux than influx. They cannot cross the BBB and are, thus, apparent substrates for ABC transporters. The strict size and charge limitation for BBB permeation results from the synergistic interaction between passive influx and active efflux.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Biophysical Chemistry (Seelig A)
UniBasel Contributors:Seelig-Löffler, Anna
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:20 Nov 2017 12:56
Deposited On:22 Mar 2012 13:36

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