Cerebral microdialysis and pharmacokinetics

Cerebral microdialysis was conceived during the 1970's by UNGERSTEDT with the aim of studying variations in neurotransmitters in different zones of the brain. The principle of cerebral or tissue microdi-alysis is to mimic the function of a blood vessel. A dialysis catheter of very small diameter (250 to 500 µm) is implanted in a tissue or organ. It is perfused using a physiological fluid. It creates an equilibrium between the extra-cellular media and the perfusion fluid. The chemical composition of the dialysate is the result of the diffusion of molecules, and is dependent on their size and on the concentration gradient, across a semi-permeable membrane..

Cerebral microdialysis has numerous advantages, including :

the use of a limited number of animals, both anaesthetised and non-anaesthetised. Each animal can be used for the whole of the study, the result being that statistical precision is improved with a minimal disturbance in homeostasis.
the dialysate is sufficiently pure as not to require extraction before quantitative analysis. It is thus possible to couple its recovery with analytical methods, such as high performance liquid chromatography, capillary electrophoresis ... Radio-immunoanalysis or enzymo-immunoanalysis can also be used directly on the samples.
only the free extra-cellular fraction, a fraction representative of the active concentration of the drug, is quantified.

Studies carried out using this model of cerebral microdialysis have essentially concerned endogenic components. Neurotransmitters, and in particular do-pamine, are the subject of numerous studies concerning the variation in their concentration at the site of action. Other studies have enabled amino-acid concentrations in various zones of the brain (hippocampus, striatum...) to be measured. More recently, cerebral microdialysis has been used with the aim of studying the mechanism of transport of exogenic components across the hemato-encephalic barrier.

It is used during studies for the development of new drugs, in pharmacodynamics and clinical pharmacology. Its use in pharmacokinetics is beginning to be envisaged. Until now, the measurement of drug transfer across the brain blood barrier was performed using post-mortem methods, such as auto-radiography or the measurement of the total fraction in the brain. These techniques are carried out on a large number of experimental animals, in order to allow for wide inter-subject variations.

In the context of SPI, the applications are multiple. The model of cerebral microdialysis, coupled to an effective analytical method, enables the pharmacokinetic evolution of the active extra-cellular fraction of a drug to be followed directly. Its use can also be valu-able during metabolism studies. Finally, this technique can be used during pharmaco-toxicological studies, for neurotoxic agents for example (e.g. case of aluminium). S.R.

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