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The role of functional pharmacology

Target verification 
Proof-of-concept 
Confirm mechanism of drug action
Strengthen predictive validity of animal models
Support "go-no go" decisions

 
Advancements in DNA and protein arrays, high-throughput screening techniques and combinatorial chemistry have revolutionized the research tools and technologies available for identification of novel drug targets, fast screening and optimization of lead compounds and characterization of selected candidate drugs by batteries of rapid in vitro tests. However, for detailed understanding of complex mechanisms of drug actions at the whole body level there is an emerging need to develop techniques allowing in vivo monitoring of drug actions on respective molecular targets and measuring biomarkers of particular disease states in animal models (Walker et al., 2004; Sams-Dodd, 2006). Ultimately, the advanced in vivo monitoring and imaging techniques may help to strengthen functional validation of candidate drugs and reduce the risk of drug failure in later phases of clinical trials.

Microdialysis and voltammetric biosensors as minimal-invasive techniques became most successful and widespread in vivo monitoring technologies in experimental neuropharmacology and neuroscience (for review, see Kehr 1999, 2007; Kehr and Yoshitake 2006). Biosensors and microdialysis probes allow monitoring of tissue chemistry (e.g. neurotransmitters, neuromodulators, trophic factors, energy suppliers) in brain but also other organs of experimental animals, typically during the course of 1-4 days. A major advantage of microdialysis is that this technique provides representative samples of all soluble molecules existing in the extracellular space, which are in the vicinity of the probe and capable to diffuse across the membrane of the dialysis probe. On the other hand, voltammetric electrodes and biosensors are mostly limited to detection of only one neurotransmitter, but offering improved temporal (second-by-second) resolution, as well as enhanced spatial resolution.  

In summary, we strongly believe that these two techniques offer currently the most powerful tools to evaluate the effects of drugs on neurotransmitter release and metabolism in vivo. Microdialysis and biosensors offer a unique possibility to study molecular basis of behaviour and efficacy of drugs on their respective therapeutic targets at the integrative (whole body) levels.

References

Kehr J (2007). New methodological aspects of microdialysis. In: Handbook of microdialysis: Methods, Applications and Perspectives. (Eds. Westerink BHC and Cremers T) Elsevier, The Netherlands. pp 111-129. 

Kehr J (1999). Monitoring chemistry of brain microenvironment: biosensors, microdialysis and related techniques, Chapter 41.  In: Modern techniques in neuroscience research (Eds. Windhorst U and Johansson H) Springer-Verlag GmbH, Heidelberg, pp 1149-1198.  

Kehr J and Yoshitake T (2006). Monitoring brain chemical signals by microdialysis. In: Encyclopedia of Sensors, vol. 6. (Eds. Grimes CA, Dickey EC and Pishko MV) American Scientific Publishers, USA. pp 287-312.

McArthur RA (2010). Value of animal models for predicting CNS therapeutic action. In: Encyclopedia of Behavioral Neuroscience, vol 3 (Eds. Koob GF, Le Moal M and Thompson RF) Oxford, Academic Press, pp 436-444.

Walker MJA, Barrett T and Guppy LJ (2004). Functional pharmacology: the drug discovery bottleneck? Drug Discovery Today: Targets, 3:208-215.



Microdialysis in drug discovery

Microdialysis data are likely to become an important part of new drug submissions and thus may potentially contribute to the FDA Critical Path Initiative to facilitate innovation in drug development.

Chaurasia et al (2007) AAPS-FDA Workshop White Paper: Microdialysis principles, application, and regulatory perspectives. J Clin Pharmacol, 47:589-603. Pharm Res, 24:1014-1025.