Physiologically Based Pharmacokinetic Modeling to Investigate Regional Brain Distribution Kinetics in Rats
Journal Title: The AAPS Journal - Year 2012, Vol 14, Issue 3
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, CSFLV, and CSFCM indicate a rapid equilibrium with plasma. However, brain ECF concentrations are on average fourfold higher than CSF concentrations, with average brain-to-plasma AUC0 − 240 ratios of 121%, 28%, and 35% for brain ECF, CSFLV, and CSFCM, 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.
Authors and Affiliations
Joost Westerhout, Bart Ploeger, Jean Smeets, Meindert Danhof, Elizabeth C. M. de Lange
Keywords
Related Articles
- EP ID EP681239
- DOI 10.1208/s12248-012-9366-1
- Views 54
- Downloads 0
A critical review of analytical ultracentrifugation and field flow fractionation methods for measuring protein aggregation
Analytical ultracentrifugation (AUC) and field flow fractionation (FFF) are 2 important biophysical methods for measuring protein aggregates. Both methods can separate protein monomer from its aggregate forms under a bro...
Virtual coupling of pyran protons in the 1H NMR spectra of C- and N-glucoronides: Dependence on substitution and solvent
We have observed that certain C-and N-glucuronides prepared as intermediates for breast cancer preventives demonstrate non-first order 1H NMR spectra that are not the result of impurities or degradation but are instead d...
Prediction of Exposure–Response Relationships to Support First-in-Human Study Design
In drug development, phase 1 first-in-human studies represent a major milestone as the drug moves from preclinical discovery to clinical development activities. The safety of human subjects is paramount to the conduct of...
Ocular Drug Delivery
Ocular drug delivery has been a major challenge to pharmacologists and drug delivery scientists due to its unique anatomy and physiology. Static barriers (different layers of cornea, sclera, and retina including blood aq...
Appropriate calibration curve fitting in ligand binding assays
Calibration curves for ligand binding assays are generally characterized by a nonlinear relationship between the mean response and the analyte concentration. Typically, the response exhibits a sigmoidal relationship with...