The development of small molecules as effective neuropharmaceuticals requires that these compounds undergo significant transport through the brain capillary endothelial wall, which makes up the blood-brain barrier (BBB) in vivo. While it is often assumed that any small molecule undergoes passive diffusion through the BBB, the evidence in the literature suggests only small molecules that (a) are lipid-soluble and (b) have a molecular weight < 400-600 Da threshold, are transported through the BBB via lipid-mediation in pharmacologically significant amounts. Exceptions to this rule are lipid-soluble molecules with a molecular weight of < 400 Da that are actively bound by plasma proteins in vivo; and small molecules that are transported through the BBB via carrier-mediated transport. This paper reviews the biology of small molecule transport through the BBB, and also reviews the various methodologies available for assessing whether small molecules undergo significant transport through the BBB in vivo. © 1995.
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