Determinants of passive drug entry into the central nervous system

1. The blood-brain barriers restrict the passive diffusion of many drugs in to the brain and constitute a significant obstacle in the pharmacological t reatment of central nervous system diseases and disorders. The degree of re striction they impose is variable, with some lipid-insoluble drugs effectiv ely excluded from the brain, while many lipid-soluble drugs do not appear t o be subject to any restriction. 2. The ease with which any particular drug diffuses across the blood-brain barrier is determined largely by the number and strength of intermolecular forces "holding" it to surrounding water molecules. By quantifying the mole cular features that contribute to these forces, it is possible to predict t he in vivo blood-brain barrier permeability of a drug from its molecular st ructure. Dipolarity, polarizability, and hydrogen bonding ability are facto rs that appear to reduce permeability, whereas molecular volume (size) and molar refraction are associated with increased permeability. 3. Increasing the passive entry of "restricted" drugs into the central nerv ous system can be achieved by disrupting the blood-brain barrier (increased paracellular diffusion) or by modifying the structure of "restricted" drug s to temporarily or permanently increase their lipid solubility (increased transcellular permeability). 4. Competitive inhibition of outwardly directed active efflux mechanisms (P -glycoprotein and MRP, the multidrug resistance-related protein) can also s ignificantly increase the accumulation of certain drugs within the central nervous system.