Physiologically based pharmacokinetic modeling to investigate regional brain distribution kinetics in rats.

The AAPS Journal
Joost WesterhoutElizabeth C M de Lange

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...Continue Reading

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Citations

Sep 12, 2013·Cell and Tissue Research·Elmira Anderzhanova, Carsten T Wotjak
Feb 14, 2013·Journal of Pharmacokinetics and Pharmacodynamics·Scott G Summerfield, Kelly C Dong
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Sep 12, 2017·CPT: Pharmacometrics & Systems Pharmacology·Yumi YamamotoElizabeth C M de Lange
Jan 27, 2019·CPT: Pharmacometrics & Systems Pharmacology·Willem J van den BrinkElizabeth C M de Lange

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