THE IMPORTANCE OF DISSOCIATION CONSTANT AND LIPID-SOLUBILITY IN INFLUENCING THE PASSAGE OF DRUGS INTO THE CEREBROSPINAL FLUID

Studies with 14 compounds indicate that the passage of drugs into cerebrospinal fluid (CSF) is governed mainly by two physical properties: the degree of ionization of the drug; and the lipidsolubility of the undissociated drug molecule. Lipid-solubility is the rate-limiting factor with drugs that are mainly undissociated at pH 7.4; these compounds penetrate the blood-CSF barrier at rates roughly related to the lipid/water partition coefficient of the undissociated molecules. The concentration of undissociated molecules is the rate-limiting factor with compounds that are highly ionized; these drugs enter the CSF at rates roughly parallel to the proportion of drug undissociated at pH 7.4. The results have been obtained with such a large number of compounds of diverse structures and physical properties that they add considerable validity to the assumption that the blood-CSF barrier behaves as an inert lipoid membrane to most foreign organic compounds.