The cerebrospinal fluid (CSF) is located within the ventricles, spinal canal, and subarachnoid spaces. The principle source of CSF are the choroid plexi of the lateral, third and fourth ventricles (Figure 6), and the volume varies between 10-20% of brain weight (Bradbury, 1979). The volume of CSF in humans is 140-150 ml, only 30-40 ml actually in the ventricular system, with a production rate of 21 ml/hr. The turnover rate of total CSF is species dependent and varies between approximately 1 hr for rat and 5 hr for human (Davson and Segal, 1996). The majority of the CSF is in the subarachnoid space, where the arachnoid membranes bridge the sulci of the brain, in the basal cisterns and around the spinal cord. CSF moves within the ventricles and subarachnoid spaces under the influence of hydrostatic pressure generated by it production. CSF cushions the brain, regulates brain extracellular fluid, allows for distribution of neuroactive substances, and is the "sink" that collects the waste products produced by the brain. Concentration of most molecules is greater in the brain than in the CSF, creating a physiological gradient between the two compartments. The continuous flow of CSF through the ventricular system and out over the surface of the brain provides a "sink" that reduces the steady-state concentration of a molecule penetrating into the brain and CSF (Davson et al., 1961). This "sink" effect is greater the slower a molecule moves, which makes it particularly important for lipid-insoluble molecules of large molecular radius (Davson and Segal, 1996). Few drugs gain entry into the brain via CSF uptake due to the bulk flow movement. However, azidothymidine (AZT) enters the brain through rapid distribution into the CSF and subsequent transport at the CSF-barrier via a thymidine transporter (i.e. pyrimidine nucleoside carrier) (Wu et al., 1992), such a transport is not present at the BBB (Cornford and Oldendorf, 1975).
