Are cerebrospinal fluid pharmacokinetics able to predict brain target concentrations of drugs?

by Bianca Rijkmans

Are the pharmacokinetics of cerebrospinal fluid (CSF) able to predict brain target concentrations of various drugs? What role does the blood brain barrier (BBB) play in the distribution of drugs within the central nervous system (CNS)? What is the relationship, in terms of drug distribution, between the different compartments of the brain? These are some of the questions explored in a review paper by de Lange and Danhof (2002).

Knowledge about distribution within the central nervous system is important for drugs that have brain target sites, such as antidepressants, anticonvulsants, anaesthetics, antibacterials and anticancer agents. In the clinical setting, direct measurement of the concentration of these types of drugs poses many challenges. Historically, most often drug concentrations within lumbar CSF were used as a proxy for the concentrations achieved in the brain – however the role of the blood-brain barrier and blood-CSF barrier in the complex relationship of drug distribution within the different compartments of the CNS requires further research. The compartments of note include the brain extracellular fluid (ECF), intra-cellular brain compartments, as well as ventricular and lumbar CSF.

There are multiple factors that may affect drug distribution within the CNS. Firstly, the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) affect the entry and distribution of drugs into the different CNS compartments. The BBB is found at the cerebral endothelial capillaries, which have tight junction proteins that restrict the movement of mainly hydrophilic drugs. The BCSFB is slightly more permeable than the BBB. The characteristics of these barrier systems have significant implications for the distribution of drugs in the CNS. Secondly, there may be distinct differences in the pharmacokinetics of drugs within lumbar CSF compared to ventricular CSF, due to diffusion as well as CSF dynamics. Thirdly, in terms of the physicochemical properties of drugs, the size, charge and lipophilicity of the drug affect its ability to passively diffuse. In this case, lipophilic, small and non-charged drug molecules are favoured when it comes to transcellular diffusion. On the other hand, hydrophilic, large and charged drug molecules rely more on paracellular diffusion, although this type of transport is mediated by the tight-junctions of the BBB and BCSFB, that preclude molecular transport based on size. Cerebral blood flow could also affect drugs crossing the BBB, with an increase in blood flow resulting in a greater influx of highly permeable drugs across the BBB. In addition, the extent of plasma-protein binding of a drug will affect its transport across the BBB and BCSFB. The turnover rate of CSF will also have an effect. Enzymes found at the BBB and BCSFB affect drug metabolism, which acts as a barrier for drug entry into the brain. In addition, pathological brain conditions can affect the permeability of the BBB. This creates repercussions for the transport of drugs across the barrier into the brain. Drugs can also cross the BBB and BCSFB by active transport, which involves the use of ion channels and pumps, including influx and efflux transporters. Some endogenous influx transporter proteins may assist drug entry into the brain, and efflux transporters may actively pump drugs out of the brain.

Considering the multitude of factors that affect drug distribution within the different CNS compartments, it seems logical to try to find a method of measuring drug concentrations as close to their presumed site of action as possible. This is important for antibacterial drugs, where a minimum inhibitory concentration (MIC) needs to be reached in order to kill off the bacteria – for example when treating bacterial meningitis. If we are still only using lumbar CSF concentrations as a proxy for brain drug concentrations, we are in the dark about the actual drug concentrations being achieved in the affected brain tissue. This has significant implications for determining whether sufficient dosages are being prescribed in the clinical setting in order to achieve the best patient outcomes.

Most drugs that target the CNS have their target sites within extracellular regions, thus extracellular brain concentrations of these drugs provide the most relevant information. Cerebral microdialysis is a method, although invasive, that may be able to measure drug concentrations achieved at specific regions in the brain. Imaging techniques, despite having significant limitations, may be non-invasive methods for obtaining better drug concentration information as well. These techniques include positron emission tomography and magnetic resonance spectroscopy.

The review concludes that the value of CSF concentrations of drugs in predicting the effect of the drugs in the brain is highly limited, and thus methods to measure drug concentrations closer to their site of action in the brain need to be further developed.


de Lange, E. and Danhof, M., 2002. Considerations in the use of cerebrospinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting. Clinical pharmacokinetics, 41(10), pp.691-703.

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