Elizabeth (Liesbeth) de Lange, Ph.D., is head of the Target Site Equilibration Group at the Leiden Academic Centre for Drug Research, Division of Pharmacology, The Netherlands.
Microdialysis is a key technique of the future in drug development. For many years the ability to obtain temporal information on unbound tissue concentrations of drugs has been sought because it is the unbound concentration of a drug that is able to traverse membranes while also the unbound drug that can interact with its target to elicit the drug response. Moreover, it is clear that we need time-resolution data to distinguish between rate and extent of pharmacokinetic (PK) and pharmacodynamic (PD) processes (Hammarlund-Udenaes et al, 2008). Microdialysis is the only technique able to obtain such information from single subjects (Chaurasia et al 2007).
This technique makes use of a tiny microdialysis probe. The probe may be inserted into a distinct region of the tissue of interest such as the brain, liver, muscle, heart, or skin. The probe tip consists of a semipermeable membrane that allows small-enough compounds to enter the probe lumen. Perfusion of the probe with a physiological solution provides the microdialysate fluid that may be collected in distinct intervals. Ex vivo analysis of the dialysate samples permits measurement of drug concentrations by virtually every analytical technique, which contributes to the selectivity and sensitivity. Drug concentrations in the microdialysates reflect the unbound concentrations of the drug surrounding the probe tip.
Since the introduction of this technique about 30 years ago, thorough understanding has developed on optimal conditions of microdialysis experiments, as well as how to address the relationship between drug concentrations around the probe and in the microdialysates. With 30 years of practice, scientists have refined the microdialysis technique such that quantitative information on in vivo concentration-time profiles of drugs may be obtained from virtually any tissue in the body. This includes human tissues although, for ethical reasons, with some exceptions such as the brain. But recent evidence has shown that it is possible to predict human CNS PKPD relationships based on preclinically obtained brain microdialysis data (Stevens et al 2012). The recent volume Microdialysis in Drug Development, edited by Markus Müller, provides a comprehensive overview of microdialysis and its application for measuring drug distribution in drug development.
In drug development the use of animals is a prerequisite (as long as human experiments cannot take over), but we must address refinement, reduction, and replacement. Microdialysis may help with reduction, as from single subjects multiple data points can be obtained. It may help with refinement, as experiments can be performed in freely moving subjects. Finally, even in replacement, microdialysis may help: Together with advanced mathematical modeling, integrated in vivo experiments (“the mastermind approach”; see de Lange 2013) will allow the development of physiological PK(PD) models that explicitly separate drug properties and biological system characteristics (Westerhout et al 2012). Future such models may be able to predict PKPD relationships on the basis of knowledge on the physico-chemical properties of a new chemical entity alone.
Thus, microdialysis may be considered the gold standard for obtaining temporal information about unbound drug and biomarker concentrations, in health and disease conditions, in preclinical and clinical settings. It is extremely valuable to improve drug development and to aid in more effective therapies.
What microdialysis successes, case studies, applications, and/or combination with other techniques can you share?