Benefits of in vivo monitoring
- Microdialysis and biosensor techniques allow measuring the release and uptake of neurotransmitters, neuromodulators and other signaling molecules, as well as, levels of metabolites and drugs delivered into the interstitial fluid (ISF) of brain and other organs.
- Studies including PK/PD and targeted bioavailability such as penetration of a drug through the blood-brain barrier could be carried-out in an elegant way by use of multiple microdialysis probes sampling from various body compartments.
- Microdialysis offers the closest correlation of neurochemistry in vivo to behavior or to electrophysiological measures of brain activity.
- Microdialysis strengthens the predictive validity of animal models of psychiatric and neurological/neurodegenerative diseases and serves as a unique tool for investigating the mechanisms of drug actions.
- 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).
The role of functional pharmacology
- Target verification
- Confirm mechanism of drug action
- Strengthen predictive validity of animal models
- Support "go-no go" decisions
Advancements in “-omics” technologies including the high-throughput screening techniques and combinatorial chemistry have revolutionized the research tools available for identification of novel drug targets, screening and optimization of lead compounds and characterization of selected candidate drugs.
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 disease states.
Ultimately, the advanced in vivo monitoring and imaging techniques may help to strengthen the functional validation of candidate drugs and reduce the risk of drug failure in later phases of clinical trials.
Microdialysis and voltammetric biosensors as minimally 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). Microdialysis and biosensors allow monitoring the tissue chemistry in brain but also in other organs, typically during the course of 1-2 days. A major advantage of microdialysis is that this is a universal sampling technique, which generates representative samples of all soluble molecules present in the interstitial space, and which are capable to diffuse across the membrane of the dialysis probe. On the other hand, voltammetric biosensors are limited to detection of one analyte only, but offer higher temporal (second-by-second) resolution, as well as enhanced spatial resolution.
In summary, we strongly believe that microdialysis and biosensor techniques offer currently the most powerful tools to evaluate the effects of drugs on neurotransmitter release and metabolism in vivo. Microdialysis and biosensors provide a unique possibility to study molecular basis of behavior and efficacy of drugs at the integrative (whole body) levels.
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.
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.