A METHOD TO DETERMINE THE ABILITY OF DRUGS TO DIFFUSE THROUGH THE BLOOD-BRAIN-BARRIER

A method has been devised for predicting the ability of drugs to cross the blood-brain barrier. The criteria depend on the amphiphilic prope rties of a drug as reflected in its surface activity. The assessment w as made with various drugs that either penetrate or do not penetrate t he blood-brain barrier. The surface activity of these drugs was quanti fied by their Gibbs adsorption isotherms in terms of three parameters: (i) the onset of surface activity, (ii) the critical micelle concentr ation, and (iii) the surface area requirement of the drug at the air/w ater interface. A calibration diagram is proposed in which the critica l micelle concentration is plotted against the concentration required for the onset of surface activity. Three different regions are easily distinguished in this diagram: a region of very hydrophobic drugs whic h fail to enter the central nervous system because they remain adsorbe d to the membrane, a central area of less hydrophobic drugs which can cross the blood-brain barrier, and a region of relatively hydrophilic drugs which do not cross the blood-brain barrier unless applied at hig h concentrations. This diagram can be used to predict reliably the cen tral nervous system permeability of an unknown compound from a simple measurement of its Gibbs adsorption isotherm.