Title
Prediction of brain target site concentrations on the basis of CSF PK: impact of mechanisms of blood-to-brain transport and within brain distribution
Author
Westerhout, J.
Publication year
2014
Abstract
In the development of drugs for the treatment of central nervous system (CNS) disorders, the prediction of human CNS drug action is a big challenge. Direct measurement of brain extracellular fluid (brainECF) concentrations is highly restricted in human. Therefore, unbound drug concentrations in human cerebrospinal fluid (CSF) are used as a surrogate for human brainECF concentrations. Due to qualitative and quantitative differences in processes that govern the pharmacokinetics (PK) of drugs in the brain, a generally applicable relationship between CSF concentrations and brainECF concentrations does not exist. The aim of the research presented in this thesis was to develop a preclinical brain distribution model, allowing the prediction of human brain target site concentrations on the basis of preclinical data. In order to be able to build a brain distribution model understanding of time-dependent (also non-steady state) kinetics of the unbound drug in brainECF and CSF is essential. To that end, systematic studies on the inter-relationship of plasma PK, blood-brain barrier (BBB) transport, blood-CSF barrier (BCSFB) transport and intra-brain distribution were performed in the rat by implantation of microdialysis probes at multiple brain sites in individual animals.
Subject
ELSS - Earth, Life and Social Sciences
Life
Healthy Living
Food and Nutrition
Pharmacokinetics
Blood-brain barrier
Systems-based pharmacokinetic modeling
Brain extracellular fluid
Cerebrospinal fluid
Microdialysis
RAPID - Risk Assessment Products in Development
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http://resolver.tudelft.nl/uuid:76690249-7190-47c3-8830-2b9f412e4b62
TNO identifier
503477
Document type
doctoral thesis