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Translational Approaches for Predicting CNS Drug Effects Using Microdialysis

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Microdialysis in Drug Development

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 4))

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Abstract

CNS drug efficacy is largely dependent on target site kinetics of the unbound drug that may be strongly influenced by transport across the blood–brain barrier (BBB) and intracerebral distribution. It is, therefore, essential to have information on the unbound CNS target site pharmacokinetics, as this may distinctively differ from (unbound) plasma pharmacokinetics. Microdialysis studies on morphine, M3G, and M6G have shown the impact of different conditions on BBB transport and/or PK–PD relationships. Such heterogeneity in BBB transport and PK–PD relationships should be encompassed in the development of translational models that include specific expressions of the processes on the causal path between drug administration and CNS drug effects. An example on the development of a preclinical data-based translational model on dopaminergic inhibition is presented showing that microdialysis may provide critical and quantitative information on rate and extent of mechanisms between drug administration and CNS effects of a drug in different settings, which, combined with PK–PD modeling approaches, serves as the basis for generic translational models for prediction of CNS effects in varying conditions.

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  1. Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands

    Elizabeth de Lange

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  1. Allgemeines Krankenhaus, Department of Clinical Pharmacology, Medical University Vienna, Währinger Gürtel 18-20, Vienna, 1090, Austria

    Markus Müller

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de Lange, E. (2013). Translational Approaches for Predicting CNS Drug Effects Using Microdialysis. In: Müller, M. (eds) Microdialysis in Drug Development. AAPS Advances in the Pharmaceutical Sciences Series, vol 4. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4815-0_8

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