Abstract
One of the major challenges in the development of central nervous system (CNS)-targeted drugs is predicting CNS exposure in human from preclinical data. In this study, we present a methodology to investigate brain disposition in rats using a physiologically based modeling approach aiming at improving the prediction of human brain exposure. We specifically focused on quantifying regional diffusion and fluid flow processes within the brain. Acetaminophen was used as a test compound as it is not subjected to active transport processes. Microdialysis probes were implanted in striatum, for sampling brain extracellular fluid (ECF) concentrations, and in lateral ventricle (LV) and cisterna magna (CM), for sampling cerebrospinal fluid (CSF) concentrations. Serial blood samples were taken in parallel. These data, in addition to physiological parameters from literature, were used to develop a physiologically based model to describe the regional brain pharmacokinetics of acetaminophen. The concentration-time profiles of brain ECF, CSF(LV), and CSF(CM) indicate a rapid equilibrium with plasma. However, brain ECF concentrations are on average fourfold higher than CSF concentrations, with average brain-to-plasma AUC(0-240) ratios of 121%, 28%, and 35% for brain ECF, CSF(LV), and CSF(CM), respectively. It is concluded that for acetaminophen, a model compound for passive transport into, within, and out of the brain, differences exist between the brain ECF and the CSF pharmacokinetics. The physiologically based pharmacokinetic modeling approach is important, as it allowed the prediction of human brain ECF exposure on the basis of human CSF concentrations.
Highlights
Central nervous system (CNS) disorders are currently estimated to affect hundreds of millions of people worldwide [1]
Much attention has been given to blood–brain barrier (BBB) permeability, as this is assumed to be the main determinant of CNS exposure [4,5,6,7,8,9]
The experimental setup allowed for direct comparison of plasma concentrations with brain concentrations on two distinct sites, including the direct comparison of brain extracellular fluid (ECF) concentrations with cerebrospinal fluid (CSF) concentrations within a single rat
Summary
Central nervous system (CNS) disorders are currently estimated to affect hundreds of millions of people worldwide [1]. The actual problem lies in the inability to predict human (wanted and unwanted) CNS drug effects. Much attention has been given to blood–brain barrier (BBB) permeability, as this is assumed to be the main determinant of CNS exposure [4,5,6,7,8,9]. The brain is a dynamic multi-compartmental system, in which all processes of drug entry, within brain diffusion, metabolism, binding, and elimination determine actual CNS target site concentrations [3]. To be able to predict CNS drug effects in humans, a more mechanistic understanding is needed of the individual contributions of the processes involved in brain target site distribution and drug effects
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