Soon after the introduction of penicillin, it was recognized that only very low concentrations of the drug were obtained in cerebrospinal fluid (CSF) despite high blood levels.1,2 The relative exclusion of this organic acid from the brain and CSF has been attributed to the blood-brain and blood-CSF barriers, terms which imply an impedance to entry of mysterious nature. The barrier effect has been studied extensively in recent years, and it is well established that the physical properties of various substances may inhibit or enhance their ability to enter the brain and CSF.3-6 These properties, which are relevant to the transfer of compounds across all biological membranes, include: molecular size, degree of binding to serum proteins, lipid solubility, and the degree of ionization at the pH of the blood, CSF, and brain. However, the barrier effect has been shown to depend not only upon factors limiting entry into the