Research project
Towards a 3D brain drug distribution model
Development of drugs with adequate action on the brain is highly challenging. Therefore, quantitative understanding is needed on the highly complex processes that govern the concentration-profile of a drug (“pharmacokinetics”), such as transport of the drug from blood to brain and subsequent intra-brain distribution to the target site.
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- Elizabeth (Liesbeth) de Lange
The target site of a drug is the region in the brain where the drug can interact with biological target molecules that are expressed on the cells, to elicit the effect of the drug.
To provide such quantitative understanding, we have recently developed a multi-compartmental semi-physiologically-based pharmacokinetic (semi-PBPK) brain distribution model. This model is based on a system of ordinary differential equations (ODEs) to describe the pharmacokinetics of drugs in multiple physiological brain compartments (1). However, it is important to also take into account local brain distribution, as target expression in the brain can substantially differ between different brain regions. Additionally, recent insights have shown that target association and dissociation kinetics can change local pharmacokinetics (2).
To further extend our understanding of local brain drug distribution processes in the brain, we are currently exploring inclusion of partial differential equations (PDE), to include the regional brain distribution. By that we aim to integrate both the drug distribution and target interaction kinetics in a 3D manner, to ultimately improve the prediction of drug action in the brain.
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Yamamoto, Y. et al. (2016) Development of a multi-compartmental brain pharmacokinetic model and prediction of human brain target site concentrations. Submitted
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de Witte, W.E.A. et al. (2016) In vivo Target Residence Time and Kinetic Selectivity: The Association Rate Constant as Determinant. Trends Pharmacol. Sci. 37(10):831-42