Chapter 8 Translational Approaches for Predicting CNS Drug Effects Using Microdialysis Elizabeth de Lange 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 dis- tinctively 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 transla- tional models that include specific expressions of the processes on the causal path between drug administration and CNS drug effects. An example on the develop- ment of a preclinical data-based translational model on dopaminergic inhibition is presented showing that microdialysis may provide critical and quantitative infor- mation 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. 8.1 Introduction Knowledge on transport into the brain is important for drugs that directly act on targets in the central nervous system (CNS) (Westerhout et al. 2011) such as anti- convulsants, antidepressants, anesthetics, antibiotics, and antinociceptive, and E. de Lange (&) Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands e-mail: lange_l@lacdr.leidenuniv.nl M. Müller (ed.), Microdialysis in Drug Development, AAPS Advances in the Pharmaceutical Sciences Series, DOI: 10.1007/978-1-4614-4815-0_8, Ó American Association of Pharmaceutical Scientists 2013 143