Data presented supports the hypothesis that benzylpenicillin is transported actively from the cerebrospinal fluid (CSF) to blood. Benzylpenicillin is capable of moving against a concentration gradient, undergoes self-saturation indicative of a transfer maximum. and is competitively inhibited by paminohippuric acid and probenecid. The locus of this transport mechanism appears to be the choroid plexus. It further appears that active movement of penicillin from CSF to blood may add to the difficulty of obtaining therapeutic concentrations of this antibiotic in the CNS. Data presented also support the concept that the cerebrospinal fluid functions as an escape channel for polar metabolites of neuronal metabolism and various polar drugs. Once a drug or metabolite enters the CSF from blood or brain by simple diffusion, it may be rapidly removed either by a nonselective bulk flow process uia the arachnoid granulations or by an active transport mechanism.
Keyphrases Benzyl-14C-penicillin transport-cerebrospinal fluid to blood 0 Ventriculocisternal perfusion-drug administration 0 Autoradiography-radioactivity determination 0 Scintillometryanalysis Failure of many chemotherapeutic agents to penetrate the central nervous system (CNS) in therapeutically effective quantities is a problem that has been recognized for many years. Abraham et al. (1) found penicillin in the blood, bile, and saliva, but not in cerebrospinal fluid (CSF). Many investigators have since confirmed these observations. Boger et al. (2) have summarized much of this work. Ullberg (3) studied the fate and distribution of 35S-labeled benzylpenicillin using autoradiography and agreed with most of the observations made with microbiological assay methods which are summarized above.
Molecular size, pK, lipid solubility, and binding to proteins all contribute to the failure of many drugs to penetrate membrane systems such as the blood-brain and blood-CSF barriers (4). In addition to these factors,