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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.

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.

Children and adults with malignant diseases have a high risk of prevalence of the tumor in the central nervous system (CNS). As prophylaxis treatment methotrexate is often given. In order to monitor methotrexate exposure in the CNS, cerebrospinal fluid (CSF) concentrations are often measured. However, the question is in how far we can rely on CSF concentrations of methotrexate as appropriate surrogate for brain target site concentrations, especially under disease conditions.In this study, we have investigated the spatial distribution of unbound methotrexate in healthy rat brain by parallel microdialysis, with or without inhibition of Mrp/Oat/Oatp-mediated active transport processes by a co-administration of probenecid. Specifically, we have focused on the relationship between brain extracellular fluid (brainECF) and CSF concentrations. The data were used to develop a systems-based pharmacokinetic (SBPK) brain distribution model for methotrexate. This model was subsequently applied on literature data on methotrexate brain distribution in other healthy and diseased rats (brainECF), healthy dogs (CSF) and diseased children (CSF) and adults (brainECF and CSF).Important differences between brainECF and CSF kinetics were found, but we have found that inhibition of Mrp/Oat/Oatp-mediated active transport processes does not significantly influence the relationship between brainECF and CSF fluid methotrexate concentrations.It is concluded that in parallel obtained data on unbound brainECF, CSF and plasma concentrations, under dynamic conditions, combined with advanced mathematical modeling is a most valid approach to develop SBPK models that allow for revealing the mechanisms underlying the relationship between brainECF and CSF concentrations in health and disease.