Concepts and method development

Our overall goal in this project is to understand pharmacokinetic principles of drug delivery to the brain and drug disposition within the brain, focusing on unbound, pharmacologically active drug concentration.

Drug transport across the CNS and cellular barriers, with subcellular distribution in the brain parenchyma, are key processes of interest. Moreover, brain pharmacokinetic processes are also investigated on a regional level. In order to enhance the mechanistic understanding of brain target-site pharmacokinetics, several advanced methods are being developed by the group.

Neuropharmacokinetic parameters such as the unbound brain-to-plasma concentration ratio (Kp,uu,brain) and the unbound volume of distribution in brain (Vu,brain) are descriptors of BBB function and intracerebral distribution that have been established and adopted world-wide. Kp,uu,cell is another unique parameter characterizing the extent of cellular barrier transport, also developed by our group.

Microdialysis is used for quantitative evaluation of BBB transport. It is considered as the “gold standard” for measurement of unbound drug concentration in the brain. An alternative, rapid strategy has been developed based on combination of high-throughput in vitro techniques, such as brain homogenate equilibrium dialysis and brain slices, named “The Combinatory Mapping Approach” (see figure below). It can be used as a very valuable BBB screening toolbox for selection and optimization of candidate drugs in early drug discovery.

Our research is also focused on identification of desirable physicochemical properties for CNS penetration using computational models, aiming to facilitate discovery and development of novel neurotherapeutics. Integration of overall findings is directed towards the development of physiologically based mathematical models of brain drug disposition.

The Combinatory Mapping Approach. (Picture from Loryan et al., Pharm Res 2014)

Investigators: Irena Loryan and Margareta Hammarlund-Udenaes